clinical practice guideline for the management of ...candidiasis: 2016 update by the infectious...

Clinical Infectious Diseases

I D S A G U I D E L I N E

Clinical Practice Guideline for the Management ofCandidiasis: 2016 Update by the Infectious DiseasesSociety of AmericaPeter G. Pappas,1 Carol A. Kauffman,2 David R. Andes,3 Cornelius J. Clancy,4 Kieren A. Marr,5 Luis Ostrosky-Zeichner,6 Annette C. Reboli,7 Mindy G. Schuster,8

Jose A. Vazquez,9 Thomas J. Walsh,10 Theoklis E. Zaoutis,11 and Jack D. Sobel12

1University of Alabama at Birmingham; 2Veterans Affairs Ann Arbor Healthcare System and University of Michigan Medical School, Ann Arbor; 3University of Wisconsin, Madison; 4University ofPittsburgh, Pennsylvania; 5Johns Hopkins University School of Medicine, Baltimore, Maryland; 6University of Texas Health Science Center, Houston; 7Cooper Medical School of Rowan University,Camden, New Jersey; 8University of Pennsylvania, Philadelphia; 9Georgia Regents University, Augusta; 10Weill Cornell Medical Center and Cornell University, New York, New York; 11Children’sHospital of Pennsylvania, Philadelphia; and 12Harper University Hospital and Wayne State University, Detroit, Michigan

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended tosupplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to theseguidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the lightof each patient’s individual circumstances.

Keywords. candidemia; invasive candidiasis; fungal diagnostics; azoles; echinocandins.

EXECUTIVE SUMMARY

Background

Invasive infection due to Candida species is largely a conditionassociated with medical progress, and is widely recognized as amajor cause of morbidity and mortality in the healthcare envi-ronment. There are at least 15 distinctCandida species that causehuman disease, but >90% of invasive disease is caused by the5 most common pathogens, C. albicans, C. glabrata, C. tropicalis,C. parapsilosis, and C. krusei. Each of these organisms has uni-que virulence potential, antifungal susceptibility, and epidemi-ology, but taken as a whole, significant infections due to theseorganisms are generally referred to as invasive candidiasis.Mucosal Candida infections—especially those involving theoropharynx, esophagus, and vagina—are not considered tobe classically invasive disease, but they are included in theseguidelines. Since the last iteration of these guidelines in 2009[1], there have been new data pertaining to diagnosis, pre-vention, and treatment for proven or suspected invasive candi-diasis, leading to significant modifications in our treatmentrecommendations.

Summarized below are the 2016 revised recommendationsfor the management of candidiasis. Due to the guideline’s rele-vance to pediatrics, the guideline has been reviewed and

endorsed by the American Academy of Pediatrics (AAP) andthe Pediatric Infectious Diseases Society (PIDS). The MycosesStudy Group (MSG) has also endorsed these guidelines. Thepanel followed a guideline development process that has beenadopted by the Infectious Diseases Society of America(IDSA), which includes a systematic method of grading boththe quality of evidence (very low, low, moderate, and high)and the strength of the recommendation (weak or strong) [2](Figure 1). [3] The guidelines are not intended to replace clin-ical judgment in the management of individual patients. A de-tailed description of the methods, background, and evidencesummaries that support each recommendation can be foundin the full text of the guideline.

I. What Is the Treatment for Candidemia in Nonneutropenic Patients?Recommendations

1. An echinocandin (caspofungin: loading dose 70 mg, then50 mg daily; micafungin: 100 mg daily; anidulafungin: load-ing dose 200 mg, then 100 mg daily) is recommended as ini-tial therapy (strong recommendation; high-quality evidence).

2. Fluconazole, intravenous or oral, 800-mg (12 mg/kg) load-ing dose, then 400 mg (6 mg/kg) daily is an acceptable alter-native to an echinocandin as initial therapy in selectedpatients, including those who are not critically ill and whoare considered unlikely to have a fluconazole-resistant Can-dida species (strong recommendation; high-quality evidence).

3. Testing for azole susceptibility is recommended for all blood-stream and other clinically relevant Candida isolates. Testingfor echinocandin susceptibility should be considered in pa-tients who have had prior treatment with an echinocandinand among those who have infection with C. glabrata orC. parapsilosis (strong recommendation; low-quality evidence).

Received 28 October 2015; accepted 2 November 2015.Correspondence: P. G. Pappas, University of Alabama at Birmingham, Division of Infectious

Disease, 229 Tinsley Harrison Tower, 1900 University Blvd, Birmingham, AL 35294-0006([email protected]).

Clinical Infectious Diseases®

© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society ofAmerica. All rights reserved. For permissions, e-mail [email protected]: 10.1093/cid/civ933

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4. Transition from an echinocandin to fluconazole (usuallywithin 5–7 days) is recommended for patients who are clin-ically stable, have isolates that are susceptible to fluconazole(eg, C. albicans), and have negative repeat blood cultures fol-lowing initiation of antifungal therapy (strong recommenda-tion; moderate-quality evidence).

5. For infection due to C. glabrata, transition to higher-dosefluconazole 800 mg (12 mg/kg) daily or voriconazole 200–300 (3–4 mg/kg) twice daily should only be consideredamong patients with fluconazole-susceptible or voricona-zole-susceptible isolates (strong recommendation; low-qualityevidence).

6. Lipid formulation amphotericin B (AmB) (3–5 mg/kg daily)is a reasonable alternative if there is intolerance, limitedavailability, or resistance to other antifungal agents (strongrecommendation; high-quality evidence).

7. Transition from AmB to fluconazole is recommended after5–7 days among patients who have isolates that are suscepti-ble to fluconazole, who are clinically stable, and in whom

repeat cultures on antifungal therapy are negative (strong rec-ommendation; high-quality evidence).

8. Among patients with suspected azole- and echinocandin-resistant Candida infections, lipid formulation AmB (3–5mg/kg daily) is recommended (strong recommendation;low-quality evidence).

9. Voriconazole 400 mg (6 mg/kg) twice daily for 2 doses, then200 mg (3 mg/kg) twice daily is effective for candidemia, butoffers little advantage over fluconazole as initial therapy(strong recommendation; moderate-quality evidence). Vorico-nazole is recommended as step-down oral therapy for selectedcases of candidemia due to C. krusei (strong recommendation;low-quality evidence).

10. All nonneutropenic patients with candidemia should havea dilated ophthalmological examination, preferably per-formed by an ophthalmologist, within the first week afterdiagnosis (strong recommendation; low-quality evidence).

11. Follow-up blood cultures should be performed every dayor every other day to establish the time point at which

Figure 1. Approach and implications to rating the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Developmentand Evaluation (GRADE) methodology (unrestricted use of the figure granted by the US GRADE Network) [3].

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candidemia has been cleared (strong recommendation; low-quality evidence).

12. Recommended duration of therapy for candidemia withoutobvious metastatic complications is for 2 weeks after docu-mented clearance of Candida species from the bloodstreamand resolution of symptoms attributable to candidemia(strong recommendation; moderate-quality evidence).

II. Should Central Venous Catheters Be Removed in NonneutropenicPatients With Candidemia?Recommendation

13. Central venous catheters (CVCs) should be removed asearly as possible in the course of candidemia when the sourceis presumed to be the CVC and the catheter can be removedsafely; this decision should be individualized for each patient(strong recommendation; moderate-quality evidence).

III. What Is the Treatment for Candidemia in Neutropenic Patients?Recommendations

14. An echinocandin (caspofungin: loading dose 70 mg, then50 mg daily; micafungin: 100 mg daily; anidulafungin: loadingdose 200 mg, then 100 mg daily) is recommended as initialtherapy (strong recommendation; moderate-quality evidence).

15. Lipid formulation AmB, 3–5 mg/kg daily, is an effectivebut less attractive alternative because of the potential fortoxicity (strong recommendation; moderate-quality evidence).

16. Fluconazole, 800-mg (12 mg/kg) loading dose, then 400mg (6 mg/kg) daily, is an alternative for patients who arenot critically ill and have had no prior azole exposure(weak recommendation; low-quality evidence).

17. Fluconazole, 400 mg (6 mg/kg) daily, can be used for step-down therapy during persistent neutropenia in clinically sta-ble patients who have susceptible isolates and documentedbloodstream clearance (weak recommendation; low-qualityevidence).

18. Voriconazole, 400 mg (6 mg/kg) twice daily for 2 doses,then 200–300 mg (3–4 mg/kg) twice daily, can be used in sit-uations in which additional mold coverage is desired (weakrecommendation; low-quality evidence). Voriconazole canalso be used as step-down therapy during neutropenia inclinically stable patients who have had documented blood-stream clearance and isolates that are susceptible to voricona-zole (weak recommendation; low-quality evidence).

19. For infections due to C. krusei, an echinocandin, lipidformulation AmB, or voriconazole is recommended (strongrecommendation; low-quality evidence).

20. Recommended minimum duration of therapy for can-didemia without metastatic complications is 2 weeks afterdocumented clearance of Candida from the bloodstream,provided neutropenia and symptoms attributable to candide-mia have resolved (strong recommendation; low-qualityevidence).

21. Ophthalmological findings of choroidal and vitreal infec-tion are minimal until recovery from neutropenia; therefore,dilated funduscopic examinations should be performed with-in the first week after recovery from neutropenia (strong rec-ommendation; low-quality evidence).

22. In the neutropenic patient, sources of candidiasis otherthan a CVC (eg, gastrointestinal tract) predominate. Catheterremoval should be considered on an individual basis (strongrecommendation; low-quality evidence).

23. Granulocyte colony-stimulating factor (G-CSF)–mobilizedgranulocyte transfusions can be considered in cases of persis-tent candidemia with anticipated protracted neutropenia(weak recommendation; low-quality evidence).

IV. What Is the Treatment for Chronic Disseminated (Hepatosplenic)Candidiasis?Recommendations

24. Initial therapy with lipid formulation AmB, 3–5 mg/kg dailyOR an echinocandin (micafungin: 100 mg daily; caspofungin:70-mg loading dose, then 50 mg daily; or anidulafungin: 200-mg loading dose, then 100 mg daily), for several weeks is rec-ommended, followed by oral fluconazole, 400 mg (6 mg/kg)daily, for patients who are unlikely to have a fluconazole-resistant isolate (strong recommendation; low-quality evidence).

25. Therapy should continue until lesions resolve on repeatimaging, which is usually several months. Premature discon-tinuation of antifungal therapy can lead to relapse (strongrecommendation; low-quality evidence).

26. If chemotherapy or hematopoietic cell transplantation isrequired, it should not be delayed because of the presence ofchronic disseminated candidiasis, and antifungal therapyshould be continued throughout the period of high risk to pre-vent relapse (strong recommendation; low-quality evidence).

27. For patients who have debilitating persistent fevers,short-term (1–2 weeks) treatment with nonsteroidal anti-inflammatory drugs or corticosteroids can be considered(weak recommendation; low-quality evidence).

V. What Is the Role of Empiric Treatment for Suspected InvasiveCandidiasis in Nonneutropenic Patients in the Intensive Care Unit?Recommendations

28. Empiric antifungal therapy should be considered in criticallyill patients with risk factors for invasive candidiasis and noother known cause of fever and should be based on clinicalassessment of risk factors, surrogate markers for invasive can-didiasis, and/or culture data from nonsterile sites (strong rec-ommendation; moderate-quality evidence). Empiric antifungaltherapy should be started as soon as possible in patients whohave the above risk factors and who have clinical signs of sep-tic shock (strong recommendation; moderate-quality evidence).

29. Preferred empiric therapy for suspected candidiasis innonneutropenic patients in the intensive care unit (ICU) is


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an echinocandin (caspofungin: loading dose of 70 mg, then50 mg daily; micafungin: 100 mg daily; anidulafungin: load-ing dose of 200 mg, then 100 mg daily) (strong recommenda-tion; moderate-quality evidence).

30. Fluconazole, 800-mg (12 mg/kg) loading dose, then 400mg (6 mg/kg) daily, is an acceptable alternative for patientswho have had no recent azole exposure and are not colonizedwith azole-resistant Candida species (strong recommenda-tion; moderate-quality evidence).

31. Lipid formulation AmB, 3–5 mg/kg daily, is an alternativeif there is intolerance to other antifungal agents (strong rec-ommendation; low-quality evidence).

32. Recommended duration of empiric therapy for suspectedinvasive candidiasis in those patients who improve is 2weeks, the same as for treatment of documented candidemia(weak recommendation; low-quality evidence).

33. For patients who have no clinical response to empiric an-tifungal therapy at 4–5 days and who do not have subsequentevidence of invasive candidiasis after the start of empirictherapy or have a negative non-culture-based diagnosticassay with a high negative predictive value, considerationshould be given to stopping antifungal therapy (strong rec-ommendation; low-quality evidence).

VI. Should Prophylaxis Be Used to Prevent Invasive Candidiasis in theIntensive Care Unit Setting?Recommendations

34. Fluconazole, 800-mg (12 mg/kg) loading dose, then 400mg (6 mg/kg) daily, could be used in high-risk patients inadult ICUs with a high rate (>5%) of invasive candidiasis(weak recommendation; moderate-quality evidence).

35. An alternative is to give an echinocandin (caspofungin:70-mg loading dose, then 50 mg daily; anidulafungin:200-mg loading dose and then 100 mg daily; or micafun-gin: 100 mg daily) (weak recommendation; low-qualityevidence).

36. Daily bathing of ICU patients with chlorhexidine, whichhas been shown to decrease the incidence of bloodstream in-fections including candidemia, could be considered (weakrecommendation; moderate-quality evidence).

VII. What Is the Treatment for Neonatal Candidiasis, Including CentralNervous System Infection?What Is the Treatment for Invasive Candidiasis and Candidemia?

Recommendations

37. AmB deoxycholate, 1 mg/kg daily, is recommended forneonates with disseminated candidiasis (strong recommenda-tion; moderate-quality evidence).

38. Fluconazole, 12 mg/kg intravenous or oral daily, is a rea-sonable alternative in patients who have not been on flucon-azole prophylaxis (strong recommendation; moderate-qualityevidence).

39. Lipid formulation AmB, 3–5 mg/kg daily, is an alternative,but should be used with caution, particularly in the presenceof urinary tract involvement (weak recommendation; low-quality evidence).

40. Echinocandins should be used with caution and generallylimited to salvage therapy or to situations in which resistanceor toxicity preclude the use of AmB deoxycholate or flucon-azole (weak recommendation; low-quality evidence).

41. A lumbar puncture and a dilated retinal examination arerecommended in neonates with cultures positive for Candidaspecies from blood and/or urine (strong recommendation;low-quality evidence).

42. Computed tomographic or ultrasound imaging of the gen-itourinary tract, liver, and spleen should be performedif blood cultures are persistently positive for Candida species(strong recommendation; low-quality evidence).

43. CVC removal is strongly recommended (strong recommen-dation; moderate-quality evidence).

44. The recommended duration of therapy for candidemiawithout obvious metastatic complications is for 2 weeksafter documented clearance of Candida species from thebloodstream and resolution of signs attributable to candide-mia (strong recommendation; low-quality evidence).

What Is the Treatment for Central Nervous System Infections inNeonates?

Recommendations

45. For initial treatment, AmB deoxycholate, 1 mg/kg intrave-nous daily, is recommended (strong recommendation; low-quality evidence).

46. An alternative regimen is liposomal AmB, 5 mg/kg daily(strong recommendation; low-quality evidence).

47. The addition of flucytosine, 25 mg/kg 4 times daily, may beconsidered as salvage therapy in patients who have not had aclinical response to initial AmB therapy, but adverse effectsare frequent (weak recommendation; low-quality evidence).

48. For step-down treatment after the patient has responded toinitial treatment, fluconazole, 12 mg/kg daily, is recommend-ed for isolates that are susceptible to fluconazole (strong rec-ommendation; low-quality evidence).

49. Therapy should continue until all signs, symptoms, and cere-brospinal fluid (CSF) and radiological abnormalities, if present,have resolved (strong recommendation; low-quality evidence).

50. Infected central nervous system (CNS) devices, includingventriculostomy drains and shunts, should be removed if atall possible (strong recommendation; low-quality evidence).

What Are the Recommendations for Prophylaxis in the NeonatalIntensive Care Unit Setting?

Recommendations

51. In nurseries with high rates (>10%) of invasive candidiasis,intravenous or oral fluconazole prophylaxis, 3–6 mg/kg twice


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weekly for 6 weeks, in neonates with birth weights <1000 g isrecommended (strong recommendation; high-quality evidence).

52. Oral nystatin, 100 000 units 3 times daily for 6 weeks, is analternative to fluconazole in neonates with birth weights<1500 g in situations in which availability or resistancepreclude the use of fluconazole (weak recommendation;moderate-quality evidence).

53. Oral bovine lactoferrin (100 mg/day) may be effective inneonates <1500 g but is not currently available in US hospi-tals (weak recommendation; moderate-quality evidence).

VIII. What Is the Treatment for Intra-abdominal Candidiasis?Recommendations

54. Empiric antifungal therapy should be considered for pa-tients with clinical evidence of intra-abdominal infectionand significant risk factors for candidiasis, including recentabdominal surgery, anastomotic leaks, or necrotizing pancre-atitis (strong recommendation; moderate-quality evidence).

55. Treatment of intra-abdominal candidiasis should includesource control, with appropriate drainage and/or debride-ment (strong recommendation; moderate-quality evidence).

56. The choice of antifungal therapy is the same as for thetreatment of candidemia or empiric therapy for nonneutro-penic patients in the ICU (See sections I and V) (strong rec-ommendation; moderate-quality evidence).

57. The duration of therapy should be determined by adequacyof source control and clinical response (strong recommenda-tion; low-quality evidence).

IX. Does the Isolation of Candida Species From the Respiratory TractRequire Antifungal Therapy?Recommendation

58. Growth of Candida from respiratory secretions usually indi-cates colonization and rarely requires treatment with antifungaltherapy (strong recommendation; moderate-quality evidence).

X. What Is the Treatment for Candida Intravascular Infections, IncludingEndocarditis and Infections of Implantable Cardiac Devices?What Is the Treatment for Candida Endocarditis?

Recommendations

59. For native valve endocarditis, lipid formulation AmB, 3–5mg/kg daily, with or without flucytosine, 25 mg/kg 4 timesdaily, OR high-dose echinocandin (caspofungin 150 mgdaily, micafungin 150 mg daily, or anidulafungin 200 mgdaily) is recommended for initial therapy (strong recommen-dation; low-quality evidence).

60. Step-down therapy to fluconazole, 400–800 mg (6–12 mg/kg) daily, is recommended for patients who have susceptibleCandida isolates, have demonstrated clinical stability, andhave cleared Candida from the bloodstream (strong recom-mendation; low-quality evidence).

61. Oral voriconazole, 200–300 mg (3–4 mg/kg) twice daily, orposaconazole tablets, 300 mg daily, can be used as step-downtherapy for isolates that are susceptible to those agents butnot susceptible to fluconazole (weak recommendation; verylow-quality evidence).

62. Valve replacement is recommended; treatment should con-tinue for at least 6 weeks after surgery and for a longer durationin patients with perivalvular abscesses and other complications(strong recommendation; low-quality evidence).

63. For patients who cannot undergo valve replacement, long-term suppression with fluconazole, 400–800 mg (6–12 mg/kg) daily, if the isolate is susceptible, is recommended (strongrecommendation; low-quality evidence).

64. For prosthetic valve endocarditis, the same antifungal reg-imens suggested for native valve endocarditis are recom-mended (strong recommendation; low-quality evidence).Chronic suppressive antifungal therapy with fluconazole,400–800 mg (6–12 mg/kg) daily, is recommended to pre-vent recurrence (strong recommendation; low-qualityevidence).

What Is the Treatment for Candida Infection of ImplantableCardiac Devices?

Recommendations

65. For pacemaker and implantable cardiac defibrillator infec-tions, the entire device should be removed (strong recommen-dation; moderate-quality evidence).

66. Antifungal therapy is the same as that recommended fornative valve endocarditis (strong recommendation; low-quality evidence).

67. For infections limited to generator pockets, 4 weeks of an-tifungal therapy after removal of the device is recommended(strong recommendation; low-quality evidence).

68. For infections involving the wires, at least 6 weeks of anti-fungal therapy after wire removal is recommended (strongrecommendation; low-quality evidence).

69. For ventricular assist devices that cannot be removed, the an-tifungal regimen is the same as that recommended for nativevalve endocarditis (strong recommendation; low-quality evi-dence).Chronic suppressive therapy with fluconazole if the iso-late is susceptible, for as long as the device remains in place isrecommended (strong recommendation; low-quality evidence).

What Is the Treatment for Candida Suppurative Thrombophlebitis?

Recommendations

70. Catheter removal and incision and drainage or resection ofthe vein, if feasible, is recommended (strong recommenda-tion; low-quality evidence).

71. Lipid formulation AmB, 3–5 mg/kg daily, OR fluconazole,400–800 mg (6–12 mg/kg) daily, OR an echinocandin (cas-pofungin 150 mg daily, micafungin 150 mg daily, or anidu-lafungin 200 mg daily) for at least 2 weeks after candidemia


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(if present) has cleared is recommended (strong recommen-dation; low-quality evidence).

72. Step-down therapy to fluconazole, 400–800 mg (6–12 mg/kg) daily, should be considered for patients who have initiallyresponded to AmB or an echinocandin, are clinically stable,and have a fluconazole-susceptible isolate (strong recommen-dation; low-quality evidence).

73. Resolution of the thrombus can be used as evidence to dis-continue antifungal therapy if clinical and culture data aresupportive (strong recommendation; low-quality evidence).

XI. What Is the Treatment for Candida Osteoarticular Infections?What Is the Treatment for Candida Osteomyelitis?

Recommendations

74. Fluconazole, 400 mg (6 mg/kg) daily, for 6–12 months ORan echinocandin (caspofungin 50–70 mg daily, micafungin100 mg daily, or anidulafungin 100 mg daily) for at least 2weeks followed by fluconazole, 400 mg (6 mg/kg) daily, for6–12 months is recommended (strong recommendation;low-quality evidence).

75. Lipid formulation AmB, 3–5 mg/kg daily, for at least 2weeks followed by fluconazole, 400 mg (6 mg/kg) daily, for6–12 months is a less attractive alternative (weak recommen-dation; low-quality evidence).

76. Surgical debridement is recommended in selected cases(strong recommendation; low-quality evidence).

What Is the Treatment for Candida Septic Arthritis?

77. Fluconazole, 400 mg (6 mg/kg) daily, for 6 weeks OR anechinocandin (caspofungin 50–70 mg daily, micafungin 100mg daily, or anidulafungin 100 mg daily) for 2 weeks followedby fluconazole, 400 mg (6 mg/kg) daily, for at least 4 weeks isrecommended (strong recommendation; low-quality evidence).

78. Lipid formulation AmB, 3–5 mg/kg daily, for 2 weeks, fol-lowed by fluconazole, 400 mg (6 mg/kg) daily, for at least 4weeks is a less attractive alternative (weak recommendation;low-quality evidence).

79. Surgical drainage is indicated in all cases of septic arthritis(strong recommendation; moderate-quality evidence).

80. For septic arthritis involving a prosthetic device, device re-moval is recommended (strong recommendation; moderate-quality evidence).

81. If the prosthetic device cannot be removed, chronic sup-pression with fluconazole, 400 mg (6 mg/kg) daily, if the iso-late is susceptible, is recommended (strong recommendation;low-quality evidence).

XII. What Is the Treatment for Candida Endophthalmitis?What Is the General Approach to Candida Endophthalmitis?

Recommendations

82. All patients with candidemia should have a dilated retinalexamination, preferably performed by an ophthalmologist,

within the first week of therapy in nonneutropenic patientsto establish if endophthalmitis is present (strong recommen-dation; low-quality evidence). For neutropenic patients, it isrecommended to delay the examination until neutrophil re-covery (strong recommendation; low-quality evidence).

83. The extent of ocular infection (chorioretinitis with or with-out macular involvement and with or without vitritis) shouldbe determined by an ophthalmologist (strong recommenda-tion; low-quality evidence).

84. Decisions regarding antifungal treatment and surgical in-tervention should be made jointly by an ophthalmologist andan infectious diseases physician (strong recommendation;low-quality evidence).

What Is the Treatment for Candida Chorioretinitis WithoutVitritis?

Recommendations

85. For fluconazole-/voriconazole-susceptible isolates, flu-conazole, loading dose, 800 mg (12 mg/kg), then 400–800mg (6–12 mg/kg) daily OR voriconazole, loading dose 400mg (6 mg/kg) intravenous twice daily for 2 doses, then300 mg (4 mg/kg) intravenous or oral twice daily is recom-mended (strong recommendation; low-quality evidence).

86. For fluconazole-/voriconazole-resistant isolates, liposomalAmB, 3–5 mg/kg intravenous daily, with or without oral flu-cytosine, 25 mg/kg 4 times daily is recommended (strong rec-ommendation; low-quality evidence).

87. With macular involvement, antifungal agents as notedabove PLUS intravitreal injection of either AmB deoxycho-late, 5–10 µg/0.1 mL sterile water, or voriconazole, 100 µg/0.1 mL sterile water or normal saline, to ensure a prompthigh level of antifungal activity is recommended (strong rec-ommendation; low-quality evidence).

88. The duration of treatment should be at least 4–6 weeks,with the final duration depending on resolution of the lesionsas determined by repeated ophthalmological examinations(strong recommendation; low-quality evidence).

What Is the Treatment for Candida Chorioretinitis With Vitritis?

Recommendations

89. Antifungal therapy as detailed above for chorioretinitiswithout vitritis, PLUS intravitreal injection of either am-photericin B deoxycholate, 5–10 µg/0.1 mL sterile water, orvoriconazole, 100 µg/0.1 mL sterile water or normal salineis recommended (strong recommendation; low-qualityevidence).

90. Vitrectomy should be considered to decrease the burden oforganisms and to allow the removal of fungal abscesses thatare inaccessible to systemic antifungal agents (strong recom-mendation; low-quality evidence).

91. The duration of treatment should be at least 4–6 weeks,with the final duration dependent on resolution of the lesions


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as determined by repeated ophthalmological examinations(strong recommendation; low-quality evidence).

XIII. What Is the Treatment for Central Nervous System Candidiasis?Recommendations

92. For initial treatment, liposomal AmB, 5 mg/kg daily, withor without oral flucytosine, 25 mg/kg 4 times daily is recom-mended (strong recommendation; low-quality evidence).

93. For step-down therapy after the patient has responded to ini-tial treatment, fluconazole, 400–800 mg (6–12 mg/kg) daily, isrecommended (strong recommendation; low-quality evidence).

94. Therapy should continue until all signs and symptoms andCSF and radiological abnormalities have resolved (strong rec-ommendation; low-quality evidence).

95. Infected CNS devices, including ventriculostomy drains,shunts, stimulators, prosthetic reconstructive devices, and bio-polymer wafers that deliver chemotherapy should be removedif possible (strong recommendation; low-quality evidence).

96. For patients in whom a ventricular device cannot be re-moved, AmB deoxycholate could be administered throughthe device into the ventricle at a dosage ranging from 0.01mg to 0.5 mg in 2 mL 5% dextrose in water (weak recommen-dation; low-quality evidence).

XIV. What Is the Treatment for Urinary Tract Infections Due to CandidaSpecies?What Is the Treatment for Asymptomatic Candiduria?

Recommendations

97. Elimination of predisposing factors, such as indwellingbladder catheters, is recommended whenever feasible (strongrecommendation; low-quality evidence).

98. Treatment with antifungal agents is NOT recommendedunless the patient belongs to a group at high risk for dissem-ination; high-risk patients include neutropenic patients, verylow-birth-weight infants (<1500 g), and patients who willundergo urologic manipulation (strong recommendation;low-quality evidence).

99. Neutropenic patients and very low–birth-weight infantsshould be treated as recommended for candidemia (see sectionsIII and VII) (strong recommendation; low-quality evidence).

100. Patients undergoing urologic procedures should be treatedwith oral fluconazole, 400 mg (6 mg/kg) daily, OR AmB deox-ycholate, 0.3–0.6 mg/kg daily, for several days before and afterthe procedure (strong recommendation; low-quality evidence).

What Is the Treatment for Symptomatic Candida Cystitis?

Recommendations

101. For fluconazole-susceptible organisms, oral fluconazole,200 mg (3 mg/kg) daily for 2 weeks is recommended (strongrecommendation; moderate-quality evidence).

102. For fluconazole-resistant C. glabrata, AmB deoxycholate,0.3–0.6 mg/kg daily for 1–7 days OR oral flucytosine, 25 mg/

kg 4 times daily for 7–10 days is recommended (strong rec-ommendation; low-quality evidence).

103. For C. krusei, AmB deoxycholate, 0.3–0.6 mg/kg daily, for1–7 days is recommended (strong recommendation; low-quality evidence).

104. Removal of an indwelling bladder catheter, if feasible, isstrongly recommended (strong recommendation; low-qualityevidence).

105. AmB deoxycholate bladder irrigation, 50 mg/L sterilewater daily for 5 days, may be useful for treatment of cystitisdue to fluconazole-resistant species, such as C. glabrata andC. krusei (weak recommendation; low-quality evidence).

What Is the Treatment for Symptomatic Ascending CandidaPyelonephritis?

Recommendations

106. For fluconazole-susceptible organisms, oral fluconazole,200–400 mg (3–6 mg/kg) daily for 2 weeks is recommended(strong recommendation; low-quality evidence).

107. For fluconazole-resistant C. glabrata, AmB deoxycholate,0.3–0.6 mg/kg daily for 1–7 days with or without oral flucy-tosine, 25 mg/kg 4 times daily, is recommended (strong rec-ommendation; low-quality evidence).

108. For fluconazole-resistant C. glabrata, monotherapy withoral flucytosine, 25 mg/kg 4 times daily for 2 weeks, couldbe considered (weak recommendation; low-quality evidence).


110. Elimination of urinary tract obstruction is strongly rec-ommended (strong recommendation; low-quality evidence).

111. For patients who have nephrostomy tubes or stents inplace, consider removal or replacement, if feasible (weak rec-ommendation; low-quality evidence).

What Is the Treatment for Candida Urinary Tract Infection As-sociated With Fungus Balls?

Recommendations

112. Surgical intervention is strongly recommended in adults(strong recommendation; low-quality evidence).

113. Antifungal treatment as noted above for cystitis or pyelo-nephritis is recommended (strong recommendation; low-quality evidence).

114. Irrigation through nephrostomy tubes, if present, withAmB deoxycholate, 25–50 mg in 200–500 mL sterile water,is recommended (strong recommendation; low-qualityevidence).

XV. What Is the Treatment for Vulvovaginal Candidiasis?Recommendations

115. For the treatment of uncomplicated Candida vulvovagini-tis, topical antifungal agents, with no one agent superior to


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another, are recommended (strong recommendation; high-quality evidence).

116. Alternatively, for the treatment of uncomplicated Can-dida vulvovaginitis, a single 150-mg oral dose of fluconazoleis recommended (strong recommendation; high-qualityevidence).

117. For severe acute Candida vulvovaginitis, fluconazole, 150mg, given every 72 hours for a total of 2 or 3 doses, is recom-mended (strong recommendation; high-quality evidence).

118. For C. glabrata vulvovaginitis that is unresponsive to oralazoles, topical intravaginal boric acid, administered in a gel-atin capsule, 600 mg daily, for 14 days is an alternative(strong recommendation; low-quality evidence).

119. Another alternative agent for C. glabrata infection is nys-tatin intravaginal suppositories, 100 000 units daily for 14days (strong recommendation; low-quality evidence).

120. A third option for C. glabrata infection is topical 17% flu-cytosine cream alone or in combination with 3% AmB creamadministered daily for 14 days (weak recommendation; low-quality evidence).

121. For recurring vulvovaginal candidiasis, 10–14 days ofinduction therapy with a topical agent or oral fluconazole,followed by fluconazole, 150 mg weekly for 6 months, is rec-ommended (strong recommendation; high-quality evidence).

XVI. What Is the Treatment for Oropharyngeal Candidiasis?Recommendations

122. For mild disease, clotrimazole troches, 10 mg 5 timesdaily, OR miconazole mucoadhesive buccal 50-mg tablet ap-plied to the mucosal surface over the canine fossa once dailyfor 7–14 days are recommended (strong recommendation;high-quality evidence).

123. Alternatives for mild disease include nystatin suspension(100 000 U/mL) 4–6 mL 4 times daily, OR 1–2 nystatin pas-tilles (200 000 U each) 4 times daily, for 7–14 days (strongrecommendation; moderate-quality evidence).

124. For moderate to severe disease, oral fluconazole, 100–200mg daily, for 7–14 days is recommended (strong recommen-dation; high-quality evidence).

125. For fluconazole-refractory disease, itraconazole solution,200 mg once daily OR posaconazole suspension, 400 mgtwice daily for 3 days then 400 mg daily, for up to 28 daysare recommended (strong recommendation; moderate-qualityevidence).

126. Alternatives for fluconazole-refractory disease includevoriconazole, 200 mg twice daily, OR AmB deoxycholateoral suspension, 100 mg/mL 4 times daily (strong recommen-dation; moderate-quality evidence).

127. Intravenous echinocandin (caspofungin: 70-mg loadingdose, then 50 mg daily; micafungin: 100 mg daily; or anidu-lafungin: 200-mg loading dose, then 100 mg daily) OR intra-venous AmB deoxycholate, 0.3 mg/kg daily, are other

alternatives for refractory disease (weak recommendation;moderate-quality evidence).

128. Chronic suppressive therapy is usually unnecessary. If re-quired for patients who have recurrent infection, fluconazole,100 mg 3 times weekly, is recommended (strong recommen-dation; high-quality evidence).

129. For HIV-infected patients, antiretroviral therapy isstrongly recommended to reduce the incidence of recurrentinfections (strong recommendation; high-quality evidence).

130. For denture-related candidiasis, disinfection of the den-ture, in addition to antifungal therapy is recommended(strong recommendation; moderate-quality evidence).

XVII. What Is the Treatment for Esophageal Candidiasis?Recommendations

131. Systemic antifungal therapy is always required. A diag-nostic trial of antifungal therapy is appropriate beforeperforming an endoscopic examination (strong recommenda-tion; high-quality evidence).

132. Oral fluconazole, 200–400 mg (3–6 mg/kg) daily, for 14–21 days is recommended (strong recommendation; high-qual-ity evidence).

133. For patients who cannot tolerate oral therapy, intravenousfluconazole, 400 mg (6 mg/kg) daily, OR an echinocandin(micafungin, 150 mg daily, caspofungin, 70-mg loadingdose, then 50 mg daily, or anidulafungin, 200 mg daily) is rec-ommended (strong recommendation; high-quality evidence).

134. A less preferred alternative for those who cannot tolerateoral therapy is AmB deoxycholate, 0.3–0.7 mg/kg daily(strong recommendation; moderate-quality evidence).

135. Consider de-escalating to oral therapy with fluconazole200–400 mg (3–6 mg/kg) daily once the patient is able to tol-erate oral intake (strong recommendation; moderate-qualityevidence).

136. For fluconazole-refractory disease, itraconazole solution,200 mg daily, OR voriconazole, 200 mg (3 mg/kg) twicedaily either intravenous or oral, for 14–21 days is recom-mended (strong recommendation; high-quality evidence).

137. Alternatives for fluconazole-refractory disease include anechinocandin (micafungin: 150 mg daily; caspofungin: 70-mg loading dose, then 50 mg daily; or anidulafungin: 200mg daily) for 14–21 days, OR AmB deoxycholate, 0.3–0.7mg/kg daily, for 21 days (strong recommendation; high-quality evidence).

138. Posaconazole suspension, 400 mg twice daily, or extend-ed-release tablets, 300 mg once daily, could be considered forfluconazole-refractory disease (weak recommendation; low-quality evidence).

139. For patients who have recurrent esophagitis, chronic sup-pressive therapy with fluconazole, 100–200 mg 3 times week-ly, is recommended (strong recommendation; high-qualityevidence).


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INTRODUCTION

In the first section, the panel summarizes background informa-tion relevant to the topic. In the second section, the panel posesquestions regarding the management of candidiasis, evaluatesapplicable clinical trial and observational data, and makes rec-ommendations using the Grading of Recommendations Assess-ment, Development and Evaluation (GRADE) framework [2].The following 17 questions were answered:

I. What is the treatment for candidemia in nonneutropenicpatients?

II. Should central venous catheters be removed in nonneutro-penic patients with candidemia?

III. What is the treatment for candidemia in neutropenicpatients?

IV. What is the treatment for chronic disseminated (hepatos-plenic) candidiasis?

V. What is the role of empiric treatment for suspected invasivecandidiasis in nonneutropenic patients in the intensive careunit?

VI. Should prophylaxis be used to prevent invasive candidiasisin the intensive care unit setting?

VII. What is the treatment for neonatal candidiasis, includingcentral nervous system infection?

VIII. What is the treatment for intra-abdominal candidiasis?IX. Does the isolation of Candida species from the respiratorytract require antifungal therapy?

X. What is the treatment for Candida intravascular infections,including endocarditis and infections of implantable cardiacdevices?

XI. What is the treatment for Candida osteoarticularinfections?

XII. What is the treatment for Candida endophthalmitis?XIII. What is the treatment for central nervous systemcandidiasis?

XIV. What is the treatment for urinary tract infections due toCandida species?

XV. What is the treatment for vulvovaginal candidiasis?XVI. What is the treatment for oropharyngeal candidiasis?XVII. What is the treatment for esophageal candidiasis?

Infections due to Candida species are major causes of mor-bidity and mortality in humans, causing a diverse spectrum ofclinical disease ranging from superficial and mucosal infectionsto invasive disease associated with candidemia and metastaticorgan involvement. As an entity, candidemia is one of themost common healthcare-associated bloodstream infections inUS hospitals, typically ranking as the third or fourth most

common cause of healthcare–associated bloodstream infection.A recent multicenter point-prevalence survey identified Candi-da species as the most commonly isolated healthcare-associatedbloodstream pathogen [4]. Among patients with candidemiaand other forms of invasive candidiasis, non-albicans Candidaspecies constitute approximately 50% of all relevant isolates,representing a steady trend in many regions throughout theworld for more than a decade [5–12].

Among the many clinical manifestations of candidiasis, can-didemia and invasive candidiasis have been given the mostattention in clinical trials. Candidemia is associated with upto 47% attributable mortality [5–13], and this is even higheramong persons with septic shock [14]. Several authors havedemonstrated that mortality is closely linked to both timingof therapy and/or source control [14–19]. That is, earlier inter-vention with appropriate antifungal therapy and removal of acontaminated central venous catheter (CVC) or drainage of in-fected material is generally associated with better overall out-comes [14–19]. CVCs are commonly linked with candidemia,but catheters are not always the source, especially amongneutropenic patients in whom the gastrointestinal tract is acommon source. Most experts agree that thoughtful patient-specific management of CVCs is critical in the overall manage-ment of the infection [19].

The continued reliance on blood cultures, which are notori-ously insensitive as markers of disease, remains a significant ob-stacle to early intervention for this condition. The developmentof reliable nonculture assays is critical to providing the oppor-tunity for earlier intervention and more targeted antifungaltherapy among large numbers of patients in whom traditionalblood cultures are insensitive or provide untimely results [20].

Species distribution is also a significant challenge for allforms of candidiasis, and there is considerable geographic, cen-ter-to-center, and even unit-to-unit variability in the prevalenceof pathogenic Candida species [8–12]. Indeed, candidiasis is notone but rather several diseases, with each Candida species pre-senting its own unique characteristics with respect to tissue tro-pism, propensity to cause invasive disease, virulence, andantifungal susceptibility. A working knowledge of the local ep-idemiology and rates of antifungal resistance is critical in mak-ing informed therapeutic decisions while awaiting culture andsusceptibility data.

Despite the overall robust nature of the randomized con-trolled trials examining treatment of candidemia and otherforms of invasive candidiasis [21–34], no single trial has dem-onstrated clear superiority of one therapeutic agent over anoth-er. Careful analysis of these clinical data sometimes leads toconflicting conclusions. For instance, the use of amphotericinB (AmB) plus fluconazole is as least as effective as higher-dose (800 mg daily) fluconazole given alone for patients withcandidemia [22], but there is little role for this combinationin current practice, especially as echinocandins are such a safe


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and effective alternative. Similarly, voriconazole is as effective asthe strategy of sequential AmB and fluconazole for candidemia,but few would choose voriconazole in this setting as there is lit-tle advantage and potentially greater toxicity associated withusing this agent compared to other therapies [23].

The echinocandins have emerged as preferred agents formost episodes of candidemia and invasive candidiasis, withthe exception of central nervous system (CNS), eye, and urinarytract infections due to these organisms. This preference is basedon a strong safety profile, convenience, early fungicidal activity,a trend toward better outcomes based on data from individualstudies and combined analyses of candidemia studies [19, 25],and the emergence of azole-resistant Candida species. The re-cent emergence of multidrug-resistant Candida species furthercomplicates the selection of antifungal therapy for the immedi-ate future [10, 12, 35–38] as there are no good prospective datato guide therapy.

There is an abundance of clinical data generated from largerandomized clinical trials for candidemia, Candida esophagitis,oropharyngeal candidiasis, and prophylaxis studies in specialpopulations, such as patients in intensive care units (ICUs), ne-onates, and selected transplant recipients, and these studieshave led to important insights into optimal therapeutic ap-proaches in these vulnerable populations. For those with lesscommon manifestations of disease, such as osteomyelitis,endophthalmitis, and infective endocarditis, treatment recom-mendations are largely based on extrapolation from random-ized studies of patients with other forms of disease, smallretrospective series, and anecdotal reports. Thus, there is a crit-ical need to assess these data in an ongoing manner to providetimely recommendations pertaining to the management of pa-tients with these less common forms of candidiasis.

METHODS

Panel CompositionThe most recent version of the Infectious Diseases Society ofAmerica (IDSA) guideline on the management of patients withcandidiasis was published in 2009 [1]. For this update, the IDSAStandards and Practice Guidelines Committee (SPGC) con-vened a multidisciplinary panel of 12 experts in the manage-ment of patients with candidiasis. The panel consisted of 12members of IDSA, and included 11 adult infectious diseasesphysicians and 1 pediatric infectious diseases physician. Allpanel members were selected on the basis of their expertise inclinical and/or laboratory mycology with a focus on candidiasis.

Literature Review and AnalysisPanel members were each assigned to review the recent litera-ture for at least 1 topic, evaluate the evidence, determine thestrength of recommendations, and develop written evidencein support of these recommendations. PubMed, which includesMedline (1946 to present), was searched to identify relevant

studies for the Candida guideline PICO (population/patient, in-tervention/indicator, comparator/control, outcome) questions.Search strategies were developed and built by 2 independenthealth sciences librarians from the Health Sciences Library Sys-tem, University of Pittsburgh. For each PICO question, the li-brarians developed the search strategies using PubMed’scommand language and appropriate search fields. Medical Sub-ject Headings (MeSH) terms and keywords were used for themain search concepts of each PICO question. Articles in all lan-guages and all publication years were included. Initial searcheswere created and confirmed with input from the guideline com-mittee chairs and group leaders from August to November2013. The searches were finalized and delivered between lateNovember 2013 and January 2014. After the literature searcheswere performed, authors continued to review the literature andadded relevant articles as needed.

Process OverviewThe panel met face-to-face twice and conducted a series of con-ference calls over a 2-year period. The panel reviewed and dis-cussed all recommendations, their strength, and the quality ofevidence. Discrepancies were discussed and resolved, and allfinal recommendations represent a consensus opinion of the en-tire panel. For the final version of these guidelines, the panel as agroup reviewed all individual sections.

Evidence Review: The GRADE MethodGRADE is a systematic approach to guideline development thathas been described in detail elsewhere [2, 39]. The IDSA adopt-ed GRADE in 2008. In the GRADE system, the guideline panelassigns each recommendation with separate ratings for the un-derlying quality of evidence supporting the recommendationand for the strength with which the recommendation is made(Figure 1). Data from randomized controlled trials begin as“high” quality, and data from observational studies begin as“low” quality. However, the panel may judge that specific fea-tures of the data warrant decreasing or increasing the qualityof evidence rating, and GRADE provides guidance on howsuch factors should be weighed [39]. The strength assigned toa recommendation chiefly reflects the panel’s confidence thatthe benefits of following the recommendation are likely to out-weigh potential harms. While the quality of evidence is an im-portant factor in choosing recommendation strength, it is notprescriptive.

Guidelines and Conflicts of InterestThe expert panel complied with the IDSA policy on conflicts ofinterest, which requires disclosure of any financial or other inter-est that may be construed as constituting an actual, potential, orapparent conflict. Panel members were provided IDSA’s conflictsof interest disclosure statement and were asked to identify ties tocompanies developing products that may be affected by promul-gation of the guideline. Information was requested regarding em-ployment, consultancies, stock ownership, honoraria, research


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funding, expert testimony, and membership on company advi-sory committees. Decisions were made on a case-by-case basisas to whether an individual’s role should be limited as a resultof a conflict. Potential conflicts of interests are listed in theAcknowledgments section.

Consensus Development Based on EvidenceThe panel obtained feedback from 3 external peer reviewers.The guidelines were reviewed and endorsed by the MSG, theAmerican Academy of Pediatrics (AAP) and the Pediatric In-fectious Diseases Society (PIDS). The guideline was reviewedand approved by the IDSA SPGC and the IDSA Board of Direc-tors prior to dissemination.

Revision DatesAt annual intervals, the panel chairs will be asked for their inputon the need to update the guideline based on an examination ofthe current literature. The IDSA SPGC will consider this inputand determine the necessity and timing of an update. If war-ranted, the entire panel or a subset thereof will be convenedto discuss potential changes.

BACKGROUND

Antifungal AgentsPharmacologic Considerations for Therapy for Candidiasis

Systemic antifungal agents shown to be effective for the treat-ment of invasive candidiasis comprise 4 major categories: thepolyenes (amphotericin B [AmB] deoxycholate, liposomalAmB, AmB lipid complex [ABLC], and amphotericin B colloi-dal dispersion [ABCD, not available in the United States]), thetriazoles (fluconazole, itraconazole, voriconazole, and posaco-nazole), the echinocandins (caspofungin, anidulafungin, andmicafungin), and flucytosine. Data from a recently completedclinical trial comparing isavuconazole to an echinocandin fortreatment of invasive candidiasis are unavailable at this time.Clinicians should become familiar with strategies to optimizeefficacy through an understanding of relevant pharmacokineticproperties.

Amphotericin B

Most experience with AmB is with the deoxycholate prepara-tion. Three lipid formulations of AmB have been developedand approved for use in humans: ABLC, ABCD, and liposomalAmB. These agents possess the same spectrum of activity asAmB deoxycholate, but daily dosing regimens and toxicity pro-files differ for each agent. The 3 lipid formulation AmB agentshave different pharmacological properties and rates of treat-ment-related adverse events and should not be interchangedwithout careful consideration. In this document, a referenceto AmB, without a specific dose or other discussion of form,should be taken to be a reference to the general use of any ofthe AmB preparations. For most forms of invasive candidiasis,the typical intravenous dosage for AmB deoxycholate is 0.5–0.7mg/kg daily, but dosages as high as 1 mg/kg daily should be

considered for invasive Candida infections caused by less sus-ceptible species, such as C. glabrata and C. krusei. The typicaldosage for lipid formulation AmB is 3–5 mg/kg daily when usedfor invasive candidiasis. Nephrotoxicity is the most common se-rious adverse effect associated with AmB deoxycholate therapy,resulting in acute kidney injury in up to 50% of recipients andan electrolyte-wasting tubular acidosis in a majority of patients[40, 41]. Lipid formulations of AmB are more expensive thanAmB deoxycholate, but all have considerably less nephrotoxici-ty [42, 43]. Most observers agree that lipid formulations, withthe exception of ABCD, have fewer infusion-related reactionsthan AmB deoxycholate. The impact of the pharmacokineticsand differences in toxicity of lipid formulations of AmB havenot been formally examined in clinical trials. We are notaware of any forms of candidiasis for which lipid formulationsof AmB are superior to AmB deoxycholate in terms of clinicalefficacy. In addition, we are not aware of any situation in whichlipid formulations should not be used, with the exception of uri-nary tract infections, because of reduced renal excretion of theseformulations. Animal model studies suggest a pharmacokineticand therapeutic advantage for liposomal AmB in the CNS [44].Data demonstrating that AmB deoxycholate–induced nephro-toxicity is associated with a 6.6-fold increase in mortality haveled many clinicians to use lipid formulations of AmB in provenor suspected candidiasis, especially among patients in a high-risk environment, such as an ICU [45].

Triazoles

Fluconazole, itraconazole, voriconazole, posaconazole, and anew expanded-spectrum triazole, isavuconazole, demonstratesimilar activity against most Candida species [46–51]. Each ofthe azoles has less activity against C. glabrata and C. kruseithan against other Candida species. All of the azole antifungalsinhibit cytochrome P450 enzymes to some degree [52]. Thus,clinicians must carefully consider the influence on a patient’sdrug regimen when adding or removing an azole. In large clin-ical trials, fluconazole demonstrated efficacy comparable to thatof AmB deoxycholate for the treatment of candidemia [21, 22]and is also considered to be standard therapy for oropharyngeal,esophageal, and vaginal candidiasis, as well as urinary tract in-fections [53, 54]. Fluconazole is readily absorbed, with oral bio-availability resulting in concentrations equal to approximately90% of those achieved by intravenous administration [55]. Ab-sorption is not affected by food consumption, gastric pH, or dis-ease state. Among the triazoles, fluconazole has the greatestpenetration into the cerebrospinal fluid (CSF) and vitreous,achieving concentrations of >70% of those in serum [56–59].For this reason, it is often used in the treatment of CNS and in-traocular Candida infections. Fluconazole achieves urine con-centrations that are 10–20 times the concentrations in serumand, thus, is the preferred treatment option for symptomaticcystitis [59]. For patients with invasive candidiasis, fluconazole


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should be administered with an average loading dose of 800 mg(12 mg/kg), followed by an average daily dose of 400 mg (6 mg/kg). The higher-dose level (800 mg daily, 12 mg/kg) is often rec-ommended for therapy of susceptible C. glabrata infections, butthis has not been validated in clinical trials. Fluconazole elimi-nation is almost entirely renal; thus, a dose reduction is neededin patients with creatinine clearance <50 mL/minute.

Itraconazole is only available in oral formulations. It has notbeen well studied for invasive candidiasis, and is generally re-served for patients with mucosal candidiasis, especially thosewho have experienced treatment failure with fluconazole [60].Gastrointestinal absorption is variable among patients and isgreater for the oral solution compared with the capsule formu-lation. Histamine receptor antagonists and proton pump inhib-itors result in decreased absorption of the capsule formulation,whereas acidic beverages enhance absorption [61]. Administra-tion of the capsule formulation with food increases absorption,but the oral solution is better absorbed on an empty stomach[62]. Oral formulations are dosed in adults at 200 mg 3 timesdaily for 3 days, then 200 mg once or twice daily thereafter.

Voriconazole has demonstrated effectiveness for both muco-sal and invasive candidiasis [23, 63]. Its clinical use has been pri-marily for step-down oral therapy in patients with infection dueto C. krusei and fluconazole-resistant, voriconazole-susceptibleC. glabrata. CSF and vitreous concentrations are >50% of serumconcentration, and voriconazole has been shown to be effica-cious in case series for these infection sites [64–66]. Voricona-zole does not accumulate in active form in the urine and thusshould not be used for urinary candidiasis. The oral bioavail-ability of voriconazole is excellent and is not affected by gastricpH, but it decreases when the drug is administered with food[67,68]. In adults, the recommended oral dosing regimen for can-didiasis includes a loading dose of 400 mg (6 mg/kg) twice dailyfor 2 doses, followed by 200–300 mg (3–4 mg/kg) twice daily.

Intravenous voriconazole is complexed to a cyclodextrin mol-ecule; after 2 loading doses of 6 mg/kg every 12 hours, a main-tenance dosage of 3–4 mg/kg every 12 hours is recommended.Because of the potential for cyclodextrin accumulation andpossible nephrotoxicity among patients with significant renaldysfunction, intravenous voriconazole is not currently recom-mended for patients with a creatinine clearance <50 mL/minute.However, retrospective examination of intravenous voricona-zole use in patients with varying degrees of renal functionbelow this cutoff value has not identified toxic effects, mitigat-ing some of these concerns [69, 70]. Oral voriconazole does notrequire dosage adjustment for renal insufficiency, but it is theonly triazole that requires dosage reduction for patients withmild to moderate hepatic impairment [71].

Common polymorphisms in the gene encoding the primarymetabolic enzyme for voriconazole result in wide variability ofserum levels [72]. Drug–drug interactions are common withvoriconazole and should be considered when initiating and

discontinuing treatment with this compound [52]. Voricona-zole has not been studied systematically in fluconazole-resistantCandida species, and with the exception of C. krusei, use is cur-rently discouraged. Each of the triazoles can be associated withuncommon side effects. However, several effects are unique tovoriconazole or more commonly associated with higher vorico-nazole concentrations, including hepatic injury, visual side ef-fects, photosensitivity, periostitis, and CNS side effects [73–75].

Posaconazole does not have an indication for primary candi-diasis therapy. It demonstrates in vitro activity against Candidaspecies that is similar to that of voriconazole, but clinical dataare inadequate to make an evidence-based recommendationfor treatment of candidiasis other than oropharyngeal candidi-asis [76]. Posaconazole is currently available as an extended-re-lease tablet, an oral suspension, and an intravenous solution.The tablet formulation, given as 300 mg twice daily for 2 doses,then 300 mg daily produces predictable serum concentrationsand excellent drug exposure and requires only once-daily dos-ing [77, 78]. The oral suspension has unpredictable bioavailabil-ity [79–81]. Intravenous posaconazole is given as 300 mg twicedaily for 2 doses, then 300 mg daily.

Isavuconazole is a recently approved expanded-spectrum tri-azole antifungal with excellent in vitro activity against Candidaspecies. Preliminary analysis of the recently completed large in-ternational double-blind trial comparing isavuconazole to anechinocandin for invasive candidiasis suggests that isavucona-zole did not meet criteria for noninferiority (personal commu-nication, Astellas US).

Echinocandins

Caspofungin, anidulafungin, and micafungin are available onlyas parenteral preparations [82–84]. The minimum inhibitoryconcentrations (MICs) of the echinocandins are low for mostCandida species, including C. glabrata and C. krusei [48–50].However, recent case series have described treatment failure as-sociated with resistant strains of C. glabrata [85, 86]. Candidaparapsilosis demonstrates innately higher MICs to the echino-candins than do most other Candida species, which raises theconcern that C. parapsilosis may be less responsive to theechinocandins.

Each of these agents has been studied for the treatment ofesophageal candidiasis [24, 87, 88] and invasive candidiasis[25–34], and each has demonstrated efficacy in these situations.Recent pooled analyses of almost exclusively nonneutropenicpatients included in randomized invasive candidiasis treatmenttrials suggest a survival advantage associated with initial echino-candin therapy [19].

All echinocandins have minimal adverse effects. The phar-macologic properties in adults are also very similar, and eachis administered once daily intravenously [82–84]. Echino-candins achieve therapeutic concentrations in all infectionsites with the exception of the eye, CNS, and urine [59]. The


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major route of elimination is nonenzymatic degradation. Noneof the echinocandins require dosage adjustment for renal insuf-ficiency or dialysis. Both caspofungin and micafungin undergominimal hepatic metabolism, but neither drug is a major sub-strate for cytochrome P450. Caspofungin is the only echinocan-din for which dosage reduction is recommended for patientswith moderate to severe hepatic dysfunction. The usual intrave-nous dosing regimens for invasive candidiasis are as follows:caspofungin: loading dose 70 mg, then 50 mg daily; anidulafun-gin: loading dose 200 mg, then 100 mg daily; and micafungin:100 mg daily (no loading dose needed).

Flucytosine

Flucytosine demonstrates broad antifungal activity against mostCandida species, with the exception of C. krusei. The com-pound is available in the United States only as an oral for-mulation. The drug has a short half-life (2.4–4.8 hours) andis ordinarily administered at a dosage of 25 mg/kg 4 timesdaily for patients with normal renal function. Flucytosinedemonstrates excellent absorption after oral administration(80%–90%), and most of the drug is excreted unchanged(microbiologically active) in the urine [89, 90]; dose adjustmentis necessary for patients with renal dysfunction [91, 92].Thecompound exhibits high penetration into the CNS and eye.Concentration-dependent toxicity results in bone marrow sup-pression and hepatitis.

Flucytosine is usually given in combination with another an-tifungal agent due to a high rate of emergence of resistance dur-ing monotherapy [93]. The most common use of flucytosine inthe setting of Candida infection is in combination with AmB forpatients with more refractory infections, such as Candida endo-carditis, meningitis, or endophthalmitis. Occasionally, it is usedfor the treatment of symptomatic urinary tract candidiasis dueto fluconazole-resistant C. glabrata [94].

Pediatric Dosing

There is considerable variation in the pharmacokinetics of an-tifungal agents between adult and pediatric patients, and thedata on dosing in pediatric patients are limited. The pharmaco-logical properties of antifungal agents in children and infantshave been reviewed in detail [95]. The optimal dose of AmB de-oxycholate in neonates has not been clearly defined; a dosage of1 mg/kg is generally used [96–98]. The safety, efficacy, areaunder the curve, and maximal concentration of ABLC 2–5mg/kg day are similar in adults and children [99]. The pharma-cokinetics of liposomal AmB in neonates and children suggestthat both volume and clearance are affected by weight [100].

Flucytosine clearance is directly proportional to glomerularfiltration rate, and infants with a very low birth weight mayaccumulate high plasma concentrations because of poor renalfunction due to immaturity [101]. Thus, the use of flucytosinewithout careful monitoring of serum drug levels is discouragedin this group of patients.

Fluconazole pharmacokinetics vary with age, and the drugis rapidly cleared in children. Thus, a daily fluconazole doseof 12 mg/kg is necessary for neonates and children [102–105].Voriconazole pharmacokinetics are also highly variable in chil-dren [106–108]. To attain plasma exposures comparable tothose in adults receiving 4 mg/kg every 12 hours, a loadingdose of intravenous voriconazole of 9 mg/kg twice daily, fol-lowed by 8 mg/kg twice daily is recommended in children.The recommended oral dose is 9 mg/kg twice daily (maximumdose 350 mg) [95, 107]. There are no data on voriconazole dos-ing in children <2 years old, and there are no pediatric studiesexamining the pharmacokinetics of the intravenous formula-tion, the oral suspension, or the extended-release tablets ofposaconazole.

Caspofungin and micafungin are approved by the US Foodand Drug Administration (FDA) for use in children. Caspofun-gin dosing is based on body surface area rather than weight. Dos-ing in children is a loading dose of 70 mg/m2, followed by 50 mg/m2/day. Preliminary studies suggest an optimal dose of caspofun-gin in neonates of 25 mg/m2/day. The current recommendationfor micafungin for invasive candidiasis is 2 mg/kg/day, with theoption to increase to 4 mg/kg/day in children <40 kg. The opti-mal dose of micafungin in neonates is unknown, but likely to be10 mg/kg/day or greater [109].Anidulafungin should be dosed at1.5 mg/kg/day for neonates and children [110–112].

Considerations During Pregnancy

AmB is the treatment of choice for invasive candidiasis in preg-nant women [113]. Fluconazole, itraconazole, posaconazole,and isavuconazole should be avoided in pregnant women, espe-cially those in the first trimester, because of the possibility ofbirth defects associated with their use. Voriconazole is con-traindicated during pregnancy because of fetal abnormalitiesobserved in animals. There are few data concerning the echino-candins; thus, their use is cautioned during pregnancy. Flucyto-sine is contraindicated during pregnancy because of fetalabnormalities observed in animals.

Therapeutic Drug Monitoring

Therapeutic drug monitoring (TDM) for itraconazole, vorico-nazole, posaconazole, and flucytosine has been shown to be use-ful for optimizing efficacy and limiting toxicity in patientsreceiving therapy for a variety of invasive fungal infections, in-cluding mucosal and invasive candidiasis [114]. The basis forTDM is widely variable concentrations among patients and astrong relationship between concentration and efficacy and/ortoxicity.

For itraconazole, when measured by high-pressure liquidchromatography (HPLC), both itraconazole and its bioactivehydroxy-itraconazole metabolite are reported, the sum ofwhich should be considered in assessing drug levels. Treatmentsuccess has been associated with concentrations ≥1 mg/L andtoxicity with concentrations >5 mg/L. Bioassay levels are 3- to


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7-fold higher than those measured by HPLC. Because of non-linear pharmacokinetics in adults and genetic differences in me-tabolism, there is both intrapatient and interpatient variabilityin serum voriconazole concentrations [115–118]. TDM shouldbe considered for patients receiving voriconazole, because drugtoxicity has been observed at higher serum concentrations andreduced clinical response has been observed at lower concentra-tions [117, 118]. The therapeutic trough concentration windowfor voriconazole is 1–5.5 mg/L. Few data are available to sup-port a specific concentration to optimize posaconazole efficacy.Flucytosine monitoring is predominantly used to prevent con-centration-associated toxicity. Peak concentrations <100 mg/Lare recommended to avoid the predictable liver and bone mar-row effects [119].

Antifungal Susceptibility Testing

Intensive efforts to develop standardized, reproducible, and rel-evant susceptibility testing methods for fungi have resulted inthe development of the Clinical and Laboratory Standards Insti-tute (CLSI) M27-A3 and the European Committee on Antimi-crobial Susceptibility Testing (EUCAST) methodologies forsusceptibility testing of yeasts [120]. Interpretive breakpointsfor susceptibility take into account the MIC, as well as pharma-cokinetic/pharmacodynamic data and animal model data. Theyare reported for each species. Breakpoints have been establishedfor most, but not all, drugs for the 5 most common Candidaspecies [47, 50, 121, 122] (Table 1).

In many instances, clinical breakpoints have decreased fromthose used previously. For example, the prior Candida clinicalbreakpoint for susceptibility to fluconazole was ≤8 mg/L. Withthe new interpretation, the susceptible value has been reduced to≤2 mg/L for C. albicans. For C. glabrata, there is no breakpointestablished for susceptibility to fluconazole, itraconazole, posa-conazole, or voriconazole (Table 1).

When there is no clinical breakpoint established, the epide-miologic cutoff value (ECV) based on an examination of thedistribution of MICs within a species can be used. The ECVis defined as the MIC value that excludes non–wild type strains,notably isolates that are likely to contain a resistant mutant [50,123]. The addition of the ECV method is particularly useful fordetecting emergence of resistance in a Candida species at aninstitution.

The susceptibility of Candida to the currently available anti-fungal agents is generally predictable if the species of the in-fecting isolate is known. Currently, antifungal resistance inC. albicans is uncommon. However, individual isolates maynot necessarily follow this general pattern [124]. Recent surveil-lance studies suggest that triazole resistance among C. glabrataisolates has increased to a degree that is it difficult to rely uponthese agents for therapy in the absence of susceptibility testing[12, 125, 126].A similar trend has begun to emerge for a smallerproportion of C. glabrata isolates and the echinocandins [35, 85,

125]. The value of susceptibility testing for other Candida spe-cies is less clear, although resistance among C. tropicalis andC. parapsilosis has been reported from tertiary care institutionsthat have extensive use of antifungal agents [127, 128]. Becauseof these trends, susceptibility testing is increasingly used toguide the management of candidemia and invasive candidiasis.

Diagnosis of CandidiasisCultures of blood or other samples collected under sterile con-ditions have long been considered diagnostic gold standards forinvasive candidiasis. Nonculture diagnostic tests, such as

Table 1. Clinical Breakpoints for Antifungal Agents Against CommonCandida Species

CandidaOrganism

Clinical Breakpoint, µg/mLa

AntifungalAgent S SDD I R

C. albicans Fluconazole ≤2 4 ≥8Itraconazole ≤0.12 0.25–0.5 ≥1Voriconazole ≤0.12 0.25–0.5 ≥1Posaconazole

Anidulafungin ≤0.25 0.5 ≥1Caspofungin ≤0.25 0.5 ≥1Micafungin ≤0.25 0.5 ≥1

C. glabrata Fluconazole 32 ≥64Itraconazole

Voriconazole

Posaconazole

Anidulafungin ≤0.12 0.25 ≥0.5Caspofungin ≤0.12 0.25 ≥0.5Micafungin ≤0.06 0.12 ≥0.25

C. parapsilosis Fluconazole ≤2 4 ≥8Itraconazole

Voriconazole ≤0.12 0.25–0.5 ≥1Posaconazole

Anidulafungin ≤2 4 ≥8Caspofungin ≤2 4 ≥8Micafungin ≤2 4 ≥8

C. tropicalis Fluconazole ≤2 4 ≥8Itraconazole

Voriconazole ≤0.12 0.25–0.5 ≥1Posaconazole


C. krusei Fluconazole

Itraconazole

Voriconazole ≤0.5 1 ≥2Posaconazole


Where no values are entered, there are insufficient data to establish clinical breakpoints.

Abbreviations: I, intermediate; MIC, minimum inhibitory concentration; R, resistant; S,susceptible; SDD, susceptible dose-dependent.a Clinical breakpoints adopted by the Clinical and Laboratory Standards Institute.


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antigen, antibody, or β-D-glucan detection assays, and poly-merase chain reaction (PCR) are now entering clinical prac-tice as adjuncts to cultures. If used and interpretedjudiciously, these tests can identify more patients with inva-sive candidiasis and better direct antifungal therapy. Tofully realize the benefits of combining culture and nonculturetests, however, clinicians must carefully consider the types ofinvasive candidiasis, understand the strengths and limitationsof each assay, and interpret test results in the context of theclinical setting.

Use of Cultures in the Diagnosis of Invasive Candidiasis

Invasive candidiasis encompasses 3 entities: candidemia in theabsence of deep-seated candidiasis, candidemia associated withdeep-seated candidiasis, and deep-seated candidiasis in the ab-sence of candidemia [20]. The distribution of these entities islikely to differ among centers; on balance, data suggest thatthe groups are approximately equal in size [129].

The overall sensitivity of blood cultures for diagnosing inva-sive candidiasis is roughly 50% [20]. The limit of detection ofblood cultures is ≤1 colony-forming unit/mL [130, 131]. Thelimit of detection for cultures is at or below that of PCR[132–135]. As such, blood cultures should be positive duringthe vast majority of active Candida bloodstream infections.They may be negative in cases of extremely low-level candide-mia, intermittent candidemia, deep-seated candidiasis that per-sists after sterilization of the bloodstream, or deep-seatedcandidiasis resulting from direct inoculation of Candida inthe absence of candidemia. Blood cultures are limited by slowturnaround times (median time to positivity of 2–3 days, rang-ing from 1 to ≥7 days), and the fact that they may become pos-itive relatively late in the disease course [130, 136]. Cultures oftissues or fluid recovered from infected sites during deep-seatedcandidiasis also exhibit poor sensitivity (often <50%) and slowturnaround times, and require invasive sampling proceduresthat may be dangerous or contraindicated due to underlyingmedical conditions [137].

Antigen and Antibody Detection

Candida antigen and anti-Candida antibody detection hasgained greater acceptance in Europe than the United States.In general, antigen detection is limited by rapid clearancefrom the bloodstream [138]. Concerns have been expressedabout the reliability of antibody detection in immunosup-pressed hosts, but assays have performed well in patients withneutropenia and cell-mediated immune defects (including he-matopoietic cell and solid organ transplant recipients) [138,139]. Serum immunoglobulin G (IgG) responses against specificantigens have typically performed better than immunoglobulinM (IgM) responses, suggesting that many patients mount am-nestic responses or have ongoing, subclinical tissue invasion[139]. The best-studied test is a combined mannan/antimannanantibody assay, which is currently approved for use in Europe,

but not the United States (Platelia Candida Ag and Ab; Bio-Rad). In a meta-analysis of 14 studies, the sensitivity/specificityfor the diagnosis of invasive candidiasis of mannan and anti-mannan IgG individually were 58%/93% and 59%/83%, respec-tively [140]. Values for the combined assay were 83% and 86%,with best performances for C. albicans, C. glabrata, and C. tro-picalis infections. In one study of candidemia, at least one testwas positive before blood culture in 73% of patients [141]. In astudy of hepatosplenic candidiasis, at least one test was positivebefore radiographic changes in 86% of patients [142]. This assayis not used widely in the United States, and its role in the diag-nosis and management of invasive candidiasis is unclear.

β-D-Glucan detection

β-D-glucan is a cell wall constituent of Candida species, Asper-gillus species, Pneumocystis jiroveci, and several other fungi. Aserum β-D-glucan assay (Fungitell; Associates of Cape Cod,East Falmouth, Massachusetts) has been approved by theFDA as an adjunct to cultures for the diagnosis of invasive fun-gal infections. True-positive results are not specific for invasivecandidiasis, but rather suggest the possibility of an invasive fun-gal infection. For this reason, among patient populations thatare also at risk for invasive mold infections, such as hematopoi-etic cell transplant recipients, β-D-glucan offers a theoretical ad-vantage over more narrow assays for candidiasis. β-D-glucandetection can identify cases of invasive candidiasis days toweeks prior to positive blood cultures, and shorten the timeto initiation of antifungal therapy [143]. Prophylactic or empiricantifungal treatment is likely to impact test performance. Onthe one hand, antifungal agents may reduce diagnostic sensitiv-ity [144–146], but decreasing β-D-glucan levels may also corre-late with responses to antifungal therapy [147].

In meta-analyses of β-D-glucan studies, the pooled sensitivityand specificity for diagnosing invasive candidiasis were 75%–

80% and 80%, respectively [144–146]. A number of issues com-plicate the interpretation of these data, including uncertaintiesabout the best cutoff value for a positive result, number of pos-itive tests required to establish a diagnosis, and optimal timingand frequency of testing among at-risk patients. There ismarked heterogeneity among studies in how they addressthese issues, as well as in patient and control populations,range and type of fungal pathogens targeted, invasive candidi-asis disease entities, distributions of Candida species, prior an-tifungal use, specific β-D-glucan assays employed, and otheraspects of study design and statistical interpretation.

The major concern about β-D-glucan detection is the poten-tial for poor specificity and false positivity, which may be par-ticularly problematic in the patient populations for whichnonculture diagnostics would be most helpful. For example,false-positive results are rare in healthy controls, but decidedlymore common among patients in an ICU [148]. Causes offalse positivity include other systemic infections, such as


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gram-positive and gram-negative bacteremia, certain antibiot-ics, such as intravenous amoxicillin-clavulanate (not availablein the United States), hemodialysis, fungal colonization, receiptof albumin or immunoglobulin, use of surgical gauze or othermaterial containing glucan, and mucositis or other disruptionsof gastrointestinal mucosa [149–154]. The specificity of β-D-glucan can be improved by requiring consecutive positive re-sults rather than a single result, but false positivity remains asignificant limitation if the above-listed factors are commonin the population tested. As an extreme example, the per-patientsensitivity/specificity and positive and negative predictive valuesof routine surveillance β-D-glucan testing in a recent study oflung transplant recipients were 64%/9% and 14%/50%, respec-tively [155]. Moreover, 90% of patients had at least one positiveβ-D-glucan result. Therefore, the test will be most useful if tar-geted to subgroups of patients whose clinical course or risk fac-tors are particularly suggestive of invasive candidiasis or otherfungal infection.

The role of β-D-glucan testing of samples other than serumin the diagnosis of invasive candidiasis is not established. Stud-ies of β-D-glucan testing of CSF reported sensitivity and specif-icity of 100% and 95%–98%, respectively, for the diagnosis ofnon-Candida fungal CNS infections [156, 157]. β-D-glucan de-tection was highly sensitive and specific in a rabbit model of he-matogenous C. albicans meningoencephalitis [158]. Limiteddata suggest that positive predictive values of β-D-glucan inbronchoalveolar lavage fluid are poor for diagnosing fungalpneumonia [159]. There are case reports for testing of samplescollected from other sites of invasive Candida infection [160].

Limited data exist pertaining to the usefulness of β-D-glucantesting in children [161]. The optimal threshold for positivity ofβ-D-glucan testing in children is not known. In studies of un-infected immunocompetent individuals, mean β-D-glucan lev-els are slightly higher in children than adults [162]. Currently, itis not recommended to use β-D-glucan testing to guide pediat-ric clinical decision making.

Polymerase Chain Reaction

Candida PCR shares many of the potential benefits and short-comings of β-D-glucan detection. Compared to cultures, PCRassays of various blood fractions have been shown to shortenthe time to diagnosis of invasive candidiasis and initiation ofantifungal therapy [134, 135]. The pooled sensitivity and specif-icity of PCR for suspected invasive candidiasis in a recent meta-analysis were 95% and 92%, respectively [134]. In probable in-vasive candidiasis, sensitivity of PCR and blood cultures was85% and 38%, respectively. The impact of antifungal agentson diagnostic sensitivity was unclear. Data among patients col-onized with Candida were surprisingly limited, but there was atrend toward lower specificity.

A major limitation of PCR studies is the lack of standardizedmethodologies and multicenter validation of assay performance.

A multicenter US study assessing the performance of a self-con-tained instrument that amplifies and detects Candida DNA byPCR and T2 magnetic resonance (T2 Biosystems, Lexington,Massachusetts), respectively, has been completed [163]. Thisassay is FDA approved, but its role in the early diagnosis andmanagement of candidemia remains unclear until more dataare available. PCR has potential advantages over β-D-glucanor antigen-antibody assays, including the capacity for speciesidentification, detection of molecular markers for drug resis-tance, and multiplex formatting. In Europe, a whole-blood,multiplex real-time PCR assay (SeptiFast, Roche) that detects19 bacteria and 6 fungi (C. albicans, C. glabrata, C. parapsilosis,C. tropicalis, C. krusei, and Aspergillus fumigatus) has been in-vestigated in several studies of sepsis and neutropenic fever.Among patients with candidemia in one study, the sensitivityof the test was 94%; the only negative result was observedwith C. famata candidemia [164]. The role of PCR in testingsamples other than blood is not established.

Nonculture Diagnostic Testing for Blood Culture–Negative

Invasive Candidiasis

The overwhelming majority of studies have examined noncul-ture diagnostics in the setting of candidemia. More limiteddata on deep-seated candidiasis demonstrate how these testsmay identify cases that are currently missed by blood cultures.In a single-center study of prospectively enrolled patients, thesensitivities/specificities of the Fungitell β-D-glucan assay anda real-time quantitative PCR assay (ViraCor-IBT, Lee’s Summit,Missouri) for invasive candidiasis were 56%/73% and 80%/70%,respectively [132]. More importantly, the sensitivities of con-temporaneously collected blood cultures, β-D-glucan assay,and PCR samples among patients with deep-seated candidiasis(mostly intra-abdominal candidiasis) were 21%, 67%, and 88%,respectively. The combination of either a positive blood cultureor positive β-D-glucan assay had sensitivity for invasive candi-diasis of 79%; a positive blood culture or positive PCR samplewas 98% sensitive. A second study investigated the serum β-D-glucan assay, Candida score (a predictive score for invasive can-didiasis based on clinical parameters and burden of Candidacolonization), and Candida colonization indices (predictivescores based on burden of colonization) among prospectivelyenrolled patients who were in surgical ICUs at 2 hospitals andwho were at particularly high risk for intra-abdominal candidi-asis [143]. The sensitivity/specificity of 2 consecutive positive β-D-glucan results was 65%/78%. In contrast, the sensitivity ofblood cultures was only 7%. In addition to identifying casesmissed by blood cultures, the β-D-glucan assay was positive amedian of 5 and 6 days prior to positive intra-abdominal cul-tures and institution of antifungal therapy, respectively. Thesensitivities of Candida scores and colonization indices werecomparable to β-D-glucan, but specificities were poorer(≤43%).


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The interpretation of specificity in these studies was compli-cated by the fact that negative controls were also at risk for in-vasive candidiasis. Therefore, it is unclear if positive test resultsfor controls were false positives (as defined in the studies) ortrue positives that were missed due to the poor sensitivity ofintra-abdominal and blood cultures. Indeed, this is a centralchallenge in assessing new diagnostics for invasive candidiasis:How can test performance be accurately measured when thegold standard is inadequate?

I. What Is the Treatment for Candidemia in Nonneutropenic Patients?Recommendations

1. An echinocandin (caspofungin: loading dose 70 mg, then50 mg daily; micafungin: 100 mg daily; anidulafungin: load-ing dose 200 mg, then 100 mg daily) is recommended as ini-tial therapy (strong recommendation; high-quality evidence).

2. Fluconazole, intravenous or oral, 800-mg (12 mg/kg) load-ing dose, then 400 mg (6 mg/kg) daily is an acceptable alter-native to an echinocandin as initial therapy in selectedpatients, including those who are not critically ill and whoare considered unlikely to have a fluconazole-resistant Can-dida species (strong recommendation; high-quality evidence).

3. Testing for azole susceptibility is recommended for allbloodstream and other clinically relevant Candida isolates.Testing for echinocandin susceptibility should be consideredin patients who have had prior treatment with an echinocan-din and among those who have infection with C. glabrataor C. parapsilosis (strong recommendation; low-qualityevidence).

4. Transition from an echinocandin to fluconazole (usuallywithin 5–7 days) is recommended for patients who are clin-ically stable, have isolates that are susceptible to fluconazole(eg, C. albicans), and have negative repeat blood cultures fol-lowing initiation of antifungal therapy (strong recommenda-tion; moderate-quality evidence).

5. For infection due to C. glabrata, transition to higher-dosefluconazole 800 mg (12 mg/kg) daily or voriconazole 200–300 (3–4 mg/kg) twice daily should only be consideredamong patients with fluconazole-susceptible or voricona-zole-susceptible isolates (strong recommendation; low-qualityevidence).

6. Lipid formulation AmB (3–5 mg/kg daily) is a reasonablealternative if there is intolerance, limited availability, or resis-tance to other antifungal agents (strong recommendation;high-quality evidence).

7. Transition from AmB to fluconazole is recommended after5–7 days among patients who have isolates that are suscepti-ble to fluconazole, who are clinically stable, and in whom re-peat cultures on antifungal therapy are negative (strongrecommendation; high-quality evidence).

8. Among patients with suspected azole- and echinocandin-resistant Candida infections, lipid formulation AmB (3–5 mg/

kg daily) is recommended (strong recommendation; low-quality evidence).

9. Voriconazole 400 mg (6 mg/kg) twice daily for 2 doses, then200 mg (3 mg/kg) twice daily is effective for candidemia, butoffers little advantage over fluconazole as initial therapy(strong recommendation; moderate-quality evidence). Vorico-nazole is recommended as step-down oral therapy for selectedcases of candidemia due to C. krusei (strong recommendation;low-quality evidence).

10. All nonneutropenic patients with candidemia should havea dilated ophthalmological examination, preferably per-formed by an ophthalmologist, within the first week after di-agnosis (strong recommendation; low-quality evidence).

11. Follow-up blood cultures should be performed every day orevery other day to establish the time point at which candide-mia has been cleared (strong recommendation; low-qualityevidence).

12. Recommended duration of therapy for candidemia withoutobvious metastatic complications is for 2 weeks after docu-mented clearance of Candida species from the bloodstreamand resolution of symptoms attributable to candidemia(strong recommendation; moderate-quality evidence).

Evidence Summary

Candidemia has emerged as one of the most common causes ofhealthcare-associated bloodstream infections, and in many UShospitals, candidemia represents the third or fourth most com-mon hospital-acquired bloodstream isolate. In most clinical set-tings, C. albicans is the most commonly isolated species, but thenon-albicans Candida species together represent approximately50% of the bloodstream isolates, and this has been a growingtrend in many hospitals throughout the world for more thana decade [8–12].

There are significant challenges in treating candidemia and in-vasive candidiasis. First, the infection is associated with highmortality. Earlier therapy is associated with better overall out-comes [14–18], but there remain significant limitations to earlydiagnosis. The development of rapid diagnostic assays has beenslow; thus, clinicians continue to rely on cultures to establish adiagnosis [20]. Second, there is considerable geographic, center-to-center, and even unit-to-unit variability of species causingcandidemia [12]; each Candida species presents its own uniquechallenges with respect to virulence, pathogenicity, and antifun-gal susceptibility. Third, despite the overall robust nature of therandomized controlled trials examining treatment of candidemiaand other forms of invasive candidiasis, no single trial has demon-strated the clear superiority of one therapeutic agent over another[19, 21–34]. Fourth, the recent emergence of multidrug-resistantCandida species will complicate the selection of antifungal therapyin the immediate future [10, 12, 35–38].

The selection of any particular agent for the treatment ofcandidemia should take into account a history of recent azole or


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echinocandin exposure, a history of intolerance to an antifungalagent, the dominant Candida species and current susceptibilitydata in a particular clinical unit, severity of illness, relevant co-morbidities, and evidence of involvement of the CNS, cardiacvalves, and/or visceral organs. The risk of mortality among pa-tients with candidemia ranges from 10% to 47% [6–8, 13], butthe actual disease-associated mortality is more likely 10%–20%,with the risk of death being related to increasing age, higherAcute Physiology and Chronic Health Evaluation II (APACHEII) scores, infecting Candida species, immunosuppressiveagents, preexisting renal dysfunction, venous catheter retention,and antifungal selection [8, 19, 165–167]. Early initiation of ef-fective antifungal therapy and source control is critical in thesuccessful treatment of candidemia, as demonstrated by datasuggesting significantly higher mortality rates among patientswith candidemia in whom antifungal therapy was delayed orconsidered inadequate, and/or in whom source control wasnot promptly attained [14, 16–18, 168].

The echinocandins demonstrate significant fungicidal activi-ty against most Candida species, and each of these agents hasdemonstrated success in approximately 70%–75% of patientsin randomized, comparative clinical trials [24–28, 31, 32]. De-spite the need for intravenous administration, their superb effi-cacy, favorable safety profile, limited drug interactions, andconcerns about fluconazole resistance have led many expertsto favor the echinocandins as initial therapy for most adult pa-tients with candidemia. Few studies comparing different echi-nocandins have been performed [28, 169], but most expertsagree that these agents are sufficiently similar to be consideredinterchangeable.

Only one study comparing an echinocandin to fluconazolehas been performed, and the results from this study suggest astrong trend toward more favorable outcomes with anidulafungincompared with fluconazole as primary therapy for candidemia[27]. In a subanalysis of patients with C. albicans infections,there was a significant improvement in global response amongthose receiving anidulafungin [31]. In another subanalysis of crit-ically ill patients from this trial, those receiving anidulafungin hadsignificantly better responses at end of therapy compared withfluconazole-treated patients [170]. A combined analysis of 7 ofthe largest randomized clinical trials comparing treatment forcandidemia and invasive candidiasis and involving almost2000 patients found that initial therapy with an echinocandinwas a significant predictor of survival [19]. This same analysisidentified higher APACHE II score, older age, and infectionwith C. tropicalis to be associated with worse outcomes andhigher mortality [19].

It has become common practice for clinicians treating pa-tients with candidemia to initiate an echinocandin, then changeto an oral azole (typically fluconazole) once the patient has be-come clinically stable [1]. A recent open-label noncomparativetrial assessed outcomes of patients who were treated with

anidulafungin for at least 5 days followed by step-down therapyto oral fluconazole or voriconazole (if the infecting organismwas susceptible) when they were clinically stable and blood cul-tures had become negative [34]. There was no difference notedin outcomes among patients who continued on anidulafunginthroughout the treatment course compared with those whowere changed to an oral azole. Smaller pilot studies fromLatin America and Asia demonstrated similar findings [33,171]. Thus, on the basis of these data and other clinical trials[22, 23, 25, 26, 28, 33, 34, 171], the Expert Panel favors step-down therapy to fluconazole or voriconazole for patients whohave improved clinically following initial therapy with an echi-nocandin, have documented clearance of Candida from thebloodstream, and who are infected with an organism that issusceptible to fluconazole (eg, C. albicans, C. parapsilosis, andC. tropicalis) or voriconazole (eg, C. krusei). This transition usu-ally occurs within 5–7 days, but this time is variable and ulti-mately dependent on patient response and clinician preference.

In many parts of the world, based on success rates reportedfrom well-designed clinical trials, fluconazole remains standardtherapy for patients with candidemia [21–23, 27]. However, inlight of recent data on the efficacy of echinocandins and increas-ing resistance to fluconazole, the Expert Panel believes that flu-conazole should be considered first-line therapy only in patientswho are hemodynamically stable, who have had no previous ex-posure to azoles, and who do not belong in a group at high riskfor C. glabrata infection, including those who are elderly, haveunderlying malignancy, or are diabetic.

In previous iterations of these guidelines, the Expert Panel fa-vored fluconazole over an echinocandin for treatment of candi-demia due to C. parapsilosis based on reports of decreased invitro activity of echinocandins against this species and of echi-nocandin resistance among some isolates [11, 12, 172–175]. Inspite of these laboratory observations, there have been no clin-ical studies that have demonstrated superiority of fluconazoleover the echinocandins for the treatment of C. parapsilosis in-fections. Moreover, recent observational data from Spain amongalmost 200 patients with candidemia due to C. parapsilosis sug-gested no difference in outcome among patients who receivedinitial treatment with an echinocandin compared with thosewho received other regimens [176]. Any recommendation sup-porting fluconazole over an echinocandin is generally based ontheoretical concerns rather than on observed therapeutic failureof the echinocandins in these patients.

Voriconazole was shown to be as effective for candidemiaand invasive candidiasis as the comparator regimen of sequen-tial therapy with AmB for 4–7 days followed by fluconazole[23]. Voriconazole possesses activity against most Candida spe-cies, including C. krusei [177, 178], but the need for more fre-quent administration, less predictable pharmacokinetics, moredrug interactions, and poor tolerance to the drug make it lessattractive for initial therapy. Parenteral voriconazole appears


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to be safe when administered to those with baseline renal dys-function, despite concerns based on possible nephrotoxicityof its vehicle (sulfobutylether β-cyclodextrin) [70]. Voricona-zole does not provide predictable activity against fluconazole-resistant C. glabrata [47, 177–179]. It does, however, fill animportant niche for patients who have fluconazole-resistant iso-lates of C. krusei, C. guilliermondii, or C. glabrata that are vor-iconazole susceptible and who are ready for transition from anechinocandin or AmB to oral therapy.

There is little role for oral itraconazole for the treatment ofcandidemia, given the similar antifungal spectrum, ease of ad-ministration, superior pharmacokinetics, and better tolerabilityof fluconazole. Posaconazole has excellent in vitro activityagainst most Candida species. The extended-release tablet andthe intravenous formulation could prove useful in the future,but currently there is no role for posaconazole in the treatmentof candidemia. The broad-spectrum azole isavuconazole dem-onstrates similar in vitro activity against Candida species, asdo voriconazole and posaconazole, and could prove useful inthe future [180].

AmB has broad activity against all Candida species with theexception of C. lusitaniae, which is frequently resistant. Lipidformulations of AmB are preferred to AmB deoxycholate andshould be considered when there is a history of intolerance toechinocandins and/or azoles, the infection is refractory toother therapy, the organism is resistant to other agents, orthere is a suspicion of infection due to non-Candida yeasts,such as Cryptococcus neoformans or Histoplasma capsulatum.Liposomal AmB, 3 mg/kg daily, has been shown to be as effec-tive as micafungin for treatment of candidemia [26].

The emergence of echinocandin-resistant and echinocan-din-/azole-resistant Candida isolates, especially C. glabrata,clearly has been documented, and this finding appears to be as-sociated with worse clinical outcomes [10, 12, 35–37, 181, 182].Fluconazole resistance is a frequent finding among echinocan-din-resistant isolates [9, 10], further complicating therapeuticchoices. There are currently no prospective data to inform a de-cision, but the Expert Panel favors lipid formulation AmB fortreatment of patients with candidemia due to proven or suspect-ed fluconazole and echinocandin-resistant (multidrug resistant)strains until more data become available.

Recent data suggest that as many as 16% of patients with can-didemia have some manifestation of ocular involvement, andsome of these patients will develop severe, sight-threatening en-dophthalmitis [70]. Thus, for all patients with candidemia, theExpert Panel strongly advises a dilated funduscopic examina-tion, preferably performed by an ophthalmologist, within thefirst week after initiation of specific antifungal therapy. Somegroups have suggested that it is possible to stratify patients ac-cording to risk in an effort to avoid performing ophthalmologicexaminations on all candidemic patients [183]. This approach ispossibly more cost-effective than examining all patients

with candidemia, but the potential benefit of early identifica-tion of endophthalmitis and prevention of visual loss far out-weighs the expense of performing a dilated funduscopicexamination.

Follow-up blood cultures every day or every other day untildemonstration of clearance of Candida from the bloodstreamare helpful to establish the appropriate duration of antifungaltherapy. If there are no metastatic complications of candidemia,the duration of therapy with systemic antifungal agents should be14 days following documented clearance of Candida species fromthe bloodstream and resolution of signs and symptoms attribut-able to infection. This recommendation is based on the results ofseveral prospective, randomized trials in which this rule has beenuniversally and successfully applied, and it is generally associatedwith few complications and relapses [21–23, 26–28, 30, 32–34].

II. Should Central Venous Catheters Be Removed in NonneutropenicPatients With Candidemia?Recommendation

13. CVCs should be removed as early as possible in the courseof candidemia when the source is presumed to be the CVCand the catheter can be removed safely; this decision shouldbe individualized for each patient (strong recommendation;moderate-quality evidence).

Evidence Summary

Central venous catheters and other intravascular devices are im-portant risk factors in the development and persistence of can-didemia in nonneutropenic patients [5, 7–9, 184]. A CVC ispresent in at least 70% of nonneutropenic patients with candi-demia at the time that the diagnostic blood culture is obtained[5, 7–9, 170, 184–187]. The relationship of candidemia to CVCshas been assumed on the basis of observation, clinical experi-ence, and an understanding of the role of biofilm in the genesisof bloodstream infections [188, 189]. That candidemia in non-neutropenic patients is commonly due to contaminated CVCsis undeniable, but there remains controversy as to how best todistinguish a catheter-associated candidemia from one that isrelated to another source, such as the gastrointestinal tract.

There have been no prospective clinical studies designed toexamine CVC management as a primary measurement relatedto outcome. Moreover, several retrospective analyses have led tovery different conclusions regarding the necessity and timing ofCVC removal in the candidemic patient [19, 190–193]. Thus,the controversy continues, with some groups arguing for astrictly individualized approach to each patient [190] and othersfor an approach that removes CVCs in all nonneutropenic can-didemic patients in whom it is safe and feasible to do so [19].Noprospective study has demonstrated a survival benefit to earlyCVC removal in patients who have candidemia, but most stud-ies have demonstrated a shorter duration of candidemia and/ora trend toward improved outcomes [14, 21–23, 27, 28, 168, 192–200]. The recent combined analysis of 7 candidemia trials


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observed a survival benefit among those who underwent CVCremoval at some time during treatment for candidemia [19].The survival benefit applied to patients across all levels of se-verity of illness as determined by APACHE II scores.

The Expert Panel members strongly believe that CVCsshould be removed if this can be performed safely when candi-demia is documented in the nonneutropenic patient. It is intu-itive that each patient with candidemia must be managedindividually with respect to CVC removal or retention, but onbalance, the bulk of data supports an approach that leads toearly removal among nonneutropenic patients in whom thecatheter is a likely source of infection.

Among neutropenic patients, the role of the gastrointestinaltract as a source for disseminated candidiasis is evident fromautopsy studies, but in an individual patient, it is difficult to de-termine the relative contributions of the gastrointestinal tract vsthe CVC as the primary source of candidemia [195, 201]. Anexception is made for candidemia due to C. parapsilosis,which is very frequently associated with CVCs [188, 189, 200,202]. A recent retrospective analysis that included mostly non-neutropenic patients underscored the influence of early CVCremoval, specifically among patients with C. parapsilosis blood-stream infection, on clinical outcome [176].

III. What Is the Treatment for Candidemia in Neutropenic Patients?Recommendations

14. An echinocandin (caspofungin: loading dose 70 mg, then50 mg daily; micafungin: 100 mg daily; anidulafungin: loadingdose 200 mg, then 100 mg daily) is recommended as initialtherapy (strong recommendation; moderate-quality evidence).

15. Lipid formulation AmB, 3–5 mg/kg daily, is an effectivebut less attractive alternative because of the potential for tox-icity (strong recommendation; moderate-quality evidence).

16. Fluconazole, 800-mg (12 mg/kg) loading dose, then 400mg (6 mg/kg) daily, is an alternative for patients who arenot critically ill and have had no prior azole exposure(weak recommendation; low-quality evidence).

17. Fluconazole, 400 mg (6 mg/kg) daily, can be used for step-down therapy during persistent neutropenia in clinically stablepatients who have susceptible isolates and documented blood-stream clearance (weak recommendation; low-quality evidence).

18. Voriconazole, 400 mg (6 mg/kg) twice daily for 2 doses,then 200–300 mg (3–4 mg/kg) twice daily, can be used in sit-uations in which additional mold coverage is desired (weakrecommendation; low-quality evidence). Voriconazole canalso be used as step-down therapy during neutropenia inclinically stable patients who have had documented blood-stream clearance and isolates that are susceptible to voricona-zole (weak recommendation; low-quality evidence).

19. For infections due to C. krusei, an echinocandin, lipid for-mulation AmB, or voriconazole is recommended (strong rec-ommendation; low-quality evidence).

20. Recommended minimum duration of therapy for candide-mia without metastatic complications is 2 weeks after docu-mented clearance of Candida from the bloodstream, providedneutropenia and symptoms attributable to candidemia have re-solved (strong recommendation; low-quality evidence).

21. Ophthalmological findings of choroidal and vitreal infec-tion are minimal until recovery from neutropenia; therefore,dilated funduscopic examinations should be performed with-in the first week after recovery from neutropenia (strong rec-ommendation; low-quality evidence).

22. In the neutropenic patient, sources of candidiasis otherthan a CVC (eg, gastrointestinal tract) predominate. Catheterremoval should be considered on an individual basis (strongrecommendation; low-quality evidence).

23. Granulocyte colony-stimulating factor (G-CSF)–mobilizedgranulocyte transfusions can be considered in cases of persis-tent candidemia with anticipated protracted neutropenia(weak recommendation; low-quality evidence).

Evidence Summary

Candidemia that develops in neutropenic patients is a life-threatening infection associated with acute disseminated candi-diasis, a sepsis-like syndrome, multiorgan failure, and death.Outcomes are particularly poor in people with protracted neu-tropenia, such as that which develops after induction therapyfor hematologic malignancies [190, 203, 204]. Candidemia asso-ciated with C. tropicalis is associated with particularly poor out-comes in neutropenic hosts. Chronic disseminated candidiasis(hepatosplenic candidiasis) can ensue as a complication of can-didemia in neutropenic patients, especially when patients withgastrointestinal tract mucositis do not receive antifungal pro-phylaxis. There are no adequately powered randomized con-trolled trials of treatment of candidemia in neutropenicpatients. The data are largely derived from single-arm studies,small subsets of randomized controlled studies that have en-rolled mostly nonneutropenic patients, and pooled outcomesfrom randomized trials [205, 206].

Historically, candidemia in neutropenic patients was treatedwith an AmB formulation. The availability of voriconazole andthe echinocandins has led to greater use of these agents, butwithout compelling clinical data. The extensive use of flucona-zole for prophylaxis to prevent invasive candidiasis in neutrope-nic patients and the lack of meaningful prospective data has ledto a diminished therapeutic role for this agent among these pa-tients, except for use as maintenance, or step-down therapyafter organism species and susceptibilities are obtained in clin-ically stable patients [207].

The numbers of neutropenic patients included in candidemiatreatment studies are small. In these trials, 50% of caspofunginrecipients vs 40% of AmB deoxycholate recipients [25], 68% ofmicafungin recipients vs 61% of liposomal AmB recipients [26],and 69% of micafungin recipients vs 64% of caspofungin


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recipients [28] with neutropenia at onset of therapy were suc-cessfully treated. The randomized controlled trial of anidulafun-gin vs fluconazole enrolled too few neutropenic patients withcandidemia to generate meaningful data regarding efficacy[27]. In 2 retrospective studies, successful outcomes for primarytreatment of neutropenic patients were reported in 64% of thosereceiving AmB deoxycholate, 64% of those receiving flucona-zole, and 68% of those receiving caspofungin [29, 208].

Additional insights can be gleaned from data derived fromstudies of empiric antifungal therapy involving febrile patientswith neutropenia who had candidemia at baseline. In these stud-ies, baseline candidemia was cleared in 73% of those treated withAmB deoxycholate vs 82% of those treated with liposomal AmB[209] and in 67% of those treated with caspofungin vs 50% ofthose treated with liposomal AmB [210]. Data from a large ran-domized trial also suggest that voriconazole is a reasonable choicefor febrile patients with neutropenia and suspected invasive can-didiasis for whom additional mold coverage is desired [211].

A systematic review was conducted to analyze available datagenerated in treatment trials and empiric therapy trials that en-rolled neutropenic patients [205].This included 17 trials that ran-domized 342 neutropenic patients with documented invasivecandidiasis. Pooling of results favored use of nonpolyenes toAmB-containing comparators. Another pooled analysis thatsummarized results of treating with micafungin or comparators(liposomal AmB or caspofungin) for candidemia in the settingof malignancy-associated neutropenia from 2 randomized trialsdemonstrated success rates ranging from 53% to 85%, but no sig-nificant differences among treatment groups [206].

On the basis of these limited data, the success rates of anti-fungal therapy for candidemia in patients with neutropenia donot appear to be substantially different from those reported in thelarge randomized trials of nonneutropenic patients. However, con-clusions may be limited by significant enrollment bias of selectedpatients. Although these data do not suggest less favorable out-comes associated with fluconazole and voriconazole, many expertsprefer lipid formulation AmB or an echinocandin, which arefungicidal, as first-line agents. Similar to the approach in nonneu-tropenic patients, the recommended duration of therapy for candi-demia in neutropenic patients is for 14 days after resolution ofattributable signs and symptoms and clearance of the bloodstreamof Candida species, provided that there has been recovery fromneutropenia. When neutropenia is protracted, an antifungal drugshould be continued until engraftment. This recommendation isbased on limited data from prospective randomized trials andhas been associated with few complications and relapses [209,210].

The management of intravascular catheters in neutropenic pa-tients with candidemia is less straightforward than in their non-neutropenic counterparts. Distinguishing gut-associated fromvascular catheter–associated candidemia can be difficult in thesepatients [201]. The data for catheter removal are less compelling,and catheter removal often creates significant intravenous access

problems. An analysis of 842 patients enrolled in 2 phase 3 treat-ment trials failed to demonstrate significant clinical benefits ofcatheter removal in multivariable analyses that adjusted for othermeasures of prognostic significance [190]. The Expert Panel sug-gests that catheter removal should be considered on an individualbasis, taking into account feasibility and risk of removal.

An extremely important factor influencing the outcome ofcandidemia in neutropenic patients is the recovery of neutro-phils during therapy. In multiple cohort studies of patientswith cancer who had candidemia, and pooled analyses of ran-domized trials, persistent neutropenia was associated with agreater chance of treatment failure [190, 203, 204, 212]. Thishas led to improvement of strategies to harvest granulocytesfrom donors (including community volunteers), using G-CSFmobilization, which has been shown to be safe and feasible[213]. Analysis of subsets of people within phase 1/2 granulo-cyte infusion studies, retrospective observations, and small co-hort studies suggest that G-CSF–mobilized granulocytetransfusions may be of benefit in patients with persistent candi-demia and prolonged neutropenia [213–215]. In a randomizedcontrolled trial, granulocyte infusions were associated with fewtoxicities, but small numbers of patients in infection subgroupslimited conclusions of efficacy [216]. The panel recommendsconsideration of granulocyte infusions in select situations,when such technology is feasible.

IV. What Is the Treatment for Chronic Disseminated (Hepatosplenic)Candidiasis?Recommendations

24. Initial therapy with lipid formulation AmB, 3–5 mg/kg dailyOR an echinocandin (micafungin: 100 mg daily; caspofungin:70-mg loading dose, then 50 mg daily; or anidulafungin: 200-mg loading dose, then 100 mg daily), for several weeks is rec-ommended, followed by oral fluconazole, 400 mg (6 mg/kg)daily, for patients who are unlikely to have a fluconazole-resistant isolate (strong recommendation; low-quality evidence).

25. Therapy should continue until lesions resolve on repeatimaging, which is usually several months. Premature discon-tinuation of antifungal therapy can lead to relapse (strongrecommendation; low-quality evidence).

26. If chemotherapy or hematopoietic cell transplantation isrequired, it should not be delayed because of the presence ofchronic disseminated candidiasis, and antifungal therapyshould be continued throughout the period of high risk to pre-vent relapse (strong recommendation; low-quality evidence).

27. For patients who have debilitating persistent fevers, shortterm (1–2 weeks) treatment with nonsteroidal anti-inflam-matory drugs or corticosteroids can be considered (weak rec-ommendation; low-quality evidence).

Evidence Summary

Chronic disseminated candidiasis is an uncommon syn-drome seen almost entirely in patients who have hematologic


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malignancies and who have just recovered from neutropenia[217–219].Candida albicans is the species most commonly iso-lated, but C. tropicalis, C. glabrata, C. krusei, and other Candidaspecies also have been implicated. Fever, right upper quadrantdiscomfort, nausea, and elevation of liver enzymes occur follow-ing return of neutrophils and persist for months unless treat-ment is initiated. Contrast-enhanced computed tomography(CT), magnetic resonance imaging (MRI), positron emissiontomography-CT (PET-CT), and sometimes ultrasound haveall been shown to be useful for diagnosis and for follow-up[217, 218, 220, 221]. Biopsy of lesions may reveal budding yeastsand hyphae, but organisms may not be seen on biopsy speci-mens and often do not grow in culture, leading some to suggestthat chronic disseminated candidiasis represents an immune re-constitution syndrome [219].

Approaches to the treatment of chronic disseminated candi-diasis are based on anecdotal case reports and open-label se-ries. Early experience with AmB was discouraging; as many asone-third of patients died within 3 months with active infec-tion, and the overall mortality was 74% [222]. With the use ofnewer antifungal agents, mortality has decreased to 21% over-all and is highly linked to relapse of leukemia [223]. Lipid for-mulations of AmB have proved more efficacious, perhapsrelated to better tissue concentrations [217, 218, 224, 225]. Flu-conazole alone or following AmB induction has been shown tobe effective [226, 227]. Increasingly, patients are receiving flu-conazole prophylaxis, and thus have an increased risk of devel-oping infection with a fluconazole-resistant organism. In thispopulation, a broader-spectrum azole or an echinocandin ismore appropriate therapy. Only a few reports note experiencewith voriconazole or posaconazole for this condition, but echi-nocandins are increasingly used to treat this infection [219,223, 228–231].

Antifungal therapy should be given until all lesions have re-solved radiographically in order to prevent relapse. MRI orPET-CT appear to be the most sensitive follow-up modalities,but are expensive [220, 221]; standard contrast-enhanced CTis less expensive and is adequate for follow-up. Additional che-motherapy and hematopoietic cell transplant should be pursuedwhen clinically appropriate and not delayed because of candidi-asis. However, antifungal therapy must be continued during theperiod of immunosuppression to prevent relapse of infection[219, 223, 228–231].

There is evidence that this syndrome could possibly be a formof immune reconstitution and that corticosteroids or anti-inflammatory agents might have a role in selected patients. Sev-eral investigators have reported rapid defervescence and im-provement in liver enzyme tests when corticosteroids havebeen given in conjunction with antifungal agents [219, 223,232, 233]. The dosage of corticosteroids has generally been0.5–1 mg/kg daily of oral prednisone. The duration of steroidtreatment, although highly variable, in most cases has been

several weeks, given as a tapering dose [232, 233]. However,the role of corticosteroids in this disease is still not clear.

V. What Is the Role of Empiric Treatment for Suspected InvasiveCandidiasis in Nonneutropenic Patients in the Intensive Care Unit?Recommendations

28. Empiric antifungal therapy should be considered in criti-cally ill patients with risk factors for invasive candidiasis andno other known cause of fever and should be based on clin-ical assessment of risk factors, surrogate markers for invasivecandidiasis, and/or culture data from nonsterile sites (strongrecommendation; moderate-quality evidence). Empiric anti-fungal therapy should be started as soon as possible in pa-tients who have the above risk factors and who haveclinical signs of septic shock (strong recommendation; mod-erate-quality evidence).

29. Preferred empiric therapy for suspected candidiasis innonneutropenic patients in the ICU is an echinocandin (cas-pofungin: loading dose of 70 mg, then 50 mg daily; micafun-gin: 100 mg daily; anidulafungin: loading dose of 200 mg,then 100 mg daily) (strong recommendation; moderate-quality evidence).

30. Fluconazole, 800-mg (12 mg/kg) loading dose, then 400mg (6 mg/kg) daily, is an acceptable alternative for patientswho have had no recent azole exposure and are not colonizedwith azole-resistant Candida species (strong recommenda-tion; moderate-quality evidence).

31. Lipid formulation AmB, 3–5 mg/kg daily, is an alternativeif there is intolerance to other antifungal agents (strong rec-ommendation; low-quality evidence).

32. Recommended duration of empiric therapy for suspectedinvasive candidiasis in those patients who improve is 2weeks, the same as for treatment of documented candidemia(weak recommendation; low-quality evidence).

33. For patients who have no clinical response to empiric an-tifungal therapy at 4–5 days and who do not have subsequentevidence of invasive candidiasis after the start of empirictherapy or have a negative non-culture-based diagnosticassay with a high negative predictive value, considerationshould be given to stopping antifungal therapy (strong rec-ommendation; low-quality evidence).

Evidence Summary

Candida species are an increasing cause of invasive infection innonneutropenic patients in the ICU; half to two-thirds of all ep-isodes of candidemia occur in an ICU [5, 14, 167,170,234].Can-dida bloodstream infections are associated with increased ICUand hospital stay [129, 235].Most estimates of attributable mor-tality rates for invasive candidiasis in this setting are 30%–40%[167, 170]. In those patients who have septic shock due to Can-dida species and who do not have adequate source control orantifungal therapy begun within 24 hours, the mortality ap-proaches 100% [14]. Prompt initiation of appropriate antifungal


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therapy has been associated with as much as a 50% reduction inmortality [14, 17, 18, 236]. Prompt and appropriate antifungaltherapy is often delayed because of the relative insensitivity ofblood cultures, the time needed for blood cultures to yield growth,the possibility of negative blood cultures with invasive abdominalcandidiasis, and the lack of specific clinical signs and symptoms.Strategies for initiating empiric antifungal therapy include anevaluation of risk factors and use of surrogate markers.

Optimal utilization of risk factors and colonization status to de-rive clinical scoring systems and the interpretation of non-culture-based diagnostic tests to identify patients with invasive candidiasisto initiate early empiric antifungal therapy have been the subjects ofmany investigations. Retrospective and single-center studies haveyielded conflicting results, depending on unique patient popula-tions. Well-designed prospective clinical trials in this area havebeen difficult to perform, andmany unanswered questions remain.

Risk factors for development of invasive candidiasis includeCandida colonization, severity of illness, exposure to broad-spectrum antibiotics, recent major surgery, particularly abdom-inal surgery, necrotizing pancreatitis, dialysis, parenteral nutri-tion, corticosteroids, and the use of CVCs [237, 238]. Empirictherapy based solely on colonization with Candida species ap-pears inadequate [16, 239]. Prospective studies evaluating theextent of Candida colonization with scores or indices havenot been shown to change management, and they are labor in-tensive and expensive [234].

Several studies have looked at prediction models to identifypatients at highest risk. These studies are characterized byhigh specificity, but low sensitivity, thus missing many patientswith candidiasis [240–242]. A subset of postsurgical patients,particularly those with recurrent gastrointestinal perforation,anastomotic leaks, or acute necrotizing pancreatitis may be atuniquely high risk for candidiasis [238, 240, 243, 244]. Themost important combination of factors in an individual patienthas not been established.

Surrogate markers that have been evaluated in the ICU set-ting include β-D-glucan, mannan-antimannan antibodies, andPCR testing. β-D-glucan appears to be more sensitive than Can-dida colonization scores or indices, but appears to have low pos-itive predictive value [245–248]. False-positive results are aproblem, as noted in the Background section. The optimal tim-ing and number of samples is unknown. In a recent prophylaxistrial of high-risk ICU patients, β-D-glucan testing performedtwice weekly identified 87% of patients with proven candidiasis[249]. Small studies basing preemptive therapy on β-D-glucantesting suggest that the high negative predictive value of thistest could be useful in excluding invasive candidiasis in theICU setting [151, 248, 250–252].

Combined mannan-antimannan testing has variable sensi-tivity and specificity [142, 253]. Real-time PCR appears tohave similar sensitivity to β-D-glucan for the diagnosis ofcandidemia, but may be more sensitive for the diagnosis of

other forms of invasive candidiasis [132]. Tests using magnet-ic biosensor technology for the rapid detection of Candidaspecies from whole-blood samples (T2 Biosystems) are alsopromising [163]. Recommendations for the clinical use ofthese tests are challenging without robust data in the at-riskICU population.

Limited clinical studies have evaluated the efficacy of empiricstrategies. Retrospective studies indicate potential for highersurvival when empiric antifungal therapy is given to high-riskpatients [254]. Prospective clinical trials of empiric antifungaltherapy in the ICU are difficult to conduct and have yieldedconflicting results. Selected older studies, including those inspecific patient populations, such as those with prior gastroin-testinal surgery or bowel perforation, demonstrated potentialbenefit [255, 256]. In a randomized clinical trial of ICU patientsat risk for invasive candidiasis and with unexplained fever, em-piric fluconazole (800 mg daily for 14 days) was not associatedwith better outcomes when compared with placebo [257]. A re-cent study comparing caspofungin to placebo among ICU pa-tients with signs of infection, Candida colonization, and clinicalrisk factors for invasive candidiasis was stopped prematurelydue to poor patient accrual, confirming the difficulty in con-ducting these trials [249].

Widespread use of antifungal agents must be balancedagainst the cost, the risk of toxicity, and the emergence of resis-tance. None of the existing clinical trials have been adequatelypowered to assess the risk of the emergence of azole or echino-candin resistance. Empiric antifungal therapy should be consid-ered in critically ill patients with risk factors for invasivecandidiasis and no other known cause of fever. Preferenceshould be given to an echinocandin in hemodynamically unsta-ble patients, those previously exposed to an azole, and in thosecolonized with azole-resistant Candida species. Fluconazolemay be considered in hemodynamically stable patients whoare colonized with azole-susceptible Candida species or whohave no prior exposure to azoles. There are no data guidingthe appropriate duration of empiric antifungal therapy amongpatients who have a clinical response to therapy, but it is logicalthat it should not differ from the treatment of documented can-didemia. Conversely, therapy can be stopped after several daysin the absence of clinical response if cultures and surrogatemarkers are negative.

VI. Should Prophylaxis Be Used to Prevent Invasive Candidiasis in theICU Setting?Recommendations

34. Fluconazole, 800-mg (12 mg/kg) loading dose, then 400mg (6 mg/kg) daily, could be used in high-risk patients inadult ICUs with a high rate (>5%) of invasive candidiasis(weak recommendation; moderate-quality evidence).

35. An alternative is to give an echinocandin (caspofungin: 70-mg loading dose, then 50 mg daily; anidulafungin: 200-mg


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loading dose and then 100 mg daily; or micafungin: 100 mgdaily) (weak recommendation; low-quality evidence).

36. Daily bathing of ICU patients with chlorhexidine, whichhas been shown to decrease the incidence of bloodstream in-fections including candidemia, could be considered (weakrecommendation; moderate-quality evidence).

Evidence Summary

Time to appropriate therapy in candidemia appears to have a sig-nificant impact on the outcome of patients with this infection [14,17, 18].However, insensitivity and significant delays using culturetechniques, as well as limitations of rapid diagnostic tests, remainfor this common cause of bloodstream infection among patientsin the ICU [258, 259].A safe and effective prophylactic strategy toprevent candidemia among high-risk patients could be of greatbenefit [260]. The approach to prophylaxis has been eitherbroad, in which all patients within the ICU setting are treated[261, 262], or selective, in which only specific high-risk groupsof patients are targeted for prophylaxis [249, 263, 264].

For ICUs that show very high rates of invasive candidiasis, inexcess of the expected rates of <5% of patients, antifungal pro-phylaxis may be warranted in selected patients who are at high-est risk [260]. Two randomized, placebo-controlled trials haveshown a reduction in the incidence of invasive candidiasis insingle units or single hospitals when fluconazole prophylaxiswas used broadly in the ICU; one study targeted all patientsin a surgical ICU [262] and, in the other, all patients receivingmechanical ventilation [261]. In both studies, Candida urinarytract infections, as well as invasive candidiasis and candidemia,were included as endpoints.

In a blinded placebo-controlled trial that enrolled a smallnumber of patients, fluconazole prophylaxis was shown to de-crease Candida intra-abdominal infections in high-risk patientsin the surgical ICU [263]. A noncomparative, open-label trialusing caspofungin prophylaxis in a small number of similarhigh-risk surgical patients also showed benefit [264]. A recentmulticenter placebo-controlled, blinded clinical trial of caspo-fungin prophylaxis targeting only those ICU patients whomet specific criteria for high risk for invasive candidiasisshowed a trend toward reduction of invasive candidiasis, butwas limited by the sample size [249].

Several meta-analyses have assessed the issue of fluconazoleprophylaxis in ICU patients [265–268]. Not surprisingly, therewere methodological differences among the studies, and therewas variation among the study populations. All 4 meta-analysesshowed that fluconazole prophylaxis was associated with a re-duction in invasive candidiasis, but only 2 showed a reduction incandidemia [267, 268]. Importantly, only one analysis showed areduction in mortality from invasive candidiasis [268]. None ofthe meta-analyses assessed the issues of adverse effects of anti-fungal agents, the emergence of resistance to fluconazole, ormajor ecological shifts in Candida species, topics of great

importance in the ICU setting. A Cochrane analysis confirmedthe importance of focusing prophylactic efforts on high-risk pa-tients, noting that the number needed to treat to prevent onecase of invasive candidiasis in the ICU setting varied from 9in high-risk patients to 188 in low-risk patients [269].

Few data exist on risk factors for candidemia in pediatric in-tensive care unit (PICU) patients. A population-based, case-control study conducted in a large tertiary care pediatric centerfound an incidence of candidemia of 3.5 per 1000 PICU admis-sions [270]. The presence of a CVC, a diagnosis of malignancy,and receipt of either vancomycin or an antianaerobic antimi-crobial agent for >3 days were independently associated withthe development of candidemia. Children who had ≥3 ofthese risk factors in different combinations had a predictedprobability of developing candidemia of between 10% and 46%.

Data are accruing on the use of skin decolonization with an-tiseptic agents in the ICU to decrease bloodstream infections,including those caused by Candida species [271–274]. Severalmulticenter randomized clinical trials have shown that dailybathing of ICU patients with chlorhexidine decreases the inci-dence of both catheter-associated and non-catheter-associatedhospital-acquired bloodstream infections [271–273]. Thesestudies were aimed primarily at evaluating the impact onmultidrug-resistant bacterial infections and provide few dataon Candida infections. However, at least one of these trialsfound a significant reduction in catheter associated Candidabloodstream infections [272]. A meta-analysis on the effectsof daily chlorhexidine bathing included 10 studies performedin an ICU setting, only one of which was a randomized con-trolled trial. The conclusion was that chlorhexidine bathing re-duced the incidence of bloodstream infections, includingcatheter-associated bacterial infections [274]. Although notproven to prevent candidemia, there is little risk to the use ofchlorhexidine in ICU patients, and this practice may provebeneficial.

VII. What Is the Treatment for Neonatal Candidiasis, Including CentralNervous System Infection?What Is the Treatment for Neonatal Invasive Candidiasis andCandidemia?

Recommendations

37. AmB deoxycholate, 1 mg/kg daily, is recommended for ne-onates with disseminated candidiasis (strong recommenda-tion; moderate-quality evidence).

38. Fluconazole, 12 mg/kg intravenous or oral daily, is a rea-sonable alternative in patients who have not been on flucon-azole prophylaxis (strong recommendation; moderate-qualityevidence).

39. Lipid formulation AmB, 3–5 mg/kg daily, is an alternative,but should be used with caution, particularly in the presenceof urinary tract involvement (weak recommendation; low-quality evidence).


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40. Echinocandins should be used with caution and generallylimited to salvage therapy or to situations in which resistanceor toxicity preclude the use of AmB deoxycholate or flucon-azole (weak recommendation; low-quality evidence).

41. A lumbar puncture and a dilated retinal examination arerecommended in neonates with cultures positive for Candidaspecies from blood and/or urine (strong recommendation;low-quality evidence).

42. CT or ultrasound imaging of the genitourinary tract, liver,and spleen should be performed if blood cultures are persis-tently positive for Candida species (strong recommendation;low-quality evidence).

43. CVC removal is strongly recommended (strong recommen-dation; moderate-quality evidence).

44. The recommended duration of therapy for candidemiawithout obvious metastatic complications is for 2 weeksafter documented clearance of Candida species from thebloodstream and resolution of signs attributable to candide-mia (strong recommendation; low-quality evidence).

Evidence Summary

Neonatal candidiasis occurs predominately in the neonatal inten-sive care unit (NICU). Candida species are the third most com-mon pathogen associated with bloodstream infection in NICUsin the United States [275]. However, the incidence of neonatalcandidiasis has decreased dramatically over the past decade[276–278]. Neonatal candidiasis is associated with significantrisk of death, neurodevelopmental impairment in extremelylow-birth-weight infants who weigh ≤1000 g, and increasedhealthcare costs [279–284]. The primary risk factor for neonatalcandidiasis is prematurity with those neonates who have an ex-tremely low birth weight at greatest risk. These infants are at highrisk to have CNS involvement as a complication of candidemia[285, 286]. Candida albicans and C. parapsilosis account for80%–90% of neonatal invasive candidiasis [278, 287].

Neonatal candidiasis differs from invasive disease in older pa-tients in that neonates are more likely to present with nonspecificor subtle signs and symptoms of infection. Candida species in-vade virtually all tissues, including the retina, brain, heart, lung,liver, spleen, and joints [288].Endocarditis is an uncommon com-plication of candidiasis in neonates. Although meningitis is seenfrequently in association with candidemia, approximately half ofneonates with Candida meningitis do not have a positive bloodculture [285]. CNS disease in the neonate typically manifests asmeningoencephalitis and should be assumed to be present inthe neonate who has candidemia and signs and symptoms sug-gesting meningoencephalitis, as CSF findings of Candida infec-tion may be unreliable. Neurodevelopmental impairment iscommon in survivors; therefore, careful follow-up of neurodeve-lopmental parameters is important [279, 281, 282, 284].

Recent studies have highlighted the significance of candiduriain the absence of candidemia in this population [281].

Extremely low-birth-weight infants with candiduria are at asubstantial risk of death or neurodevelopmental impairment.Candiduria in this population should prompt an evaluation(blood cultures, lumbar puncture, and abdominal ultrasound)for disseminated Candida infection and warrants treatment.

The recommendation to treat neonatal candidiasis with AmBdeoxycholate or fluconazole is based on small, single-center tri-als and 2 multicenter cohort studies [279, 289–291]. In contrastto adults and older children, AmB deoxycholate is well toleratedin neonates and does not seem to be associated with a high riskfor nephrotoxicity. A recent comparative effectiveness studyfound that neonates treated with AmB lipid formulations hadhigher mortality than infants treated with AmB deoxycholateor fluconazole [291]. The difference in outcomes seen withlipid AmB formulations may be related to inadequate penetra-tion of these drugs into the kidneys, inadequate dosing for pre-mature neonates, or unknown confounders. Based on thecurrent evidence, fluconazole and AmB deoxycholate are accept-able choices for therapy, and lipid formulations of AmB shouldbe used with caution. There are few data on the use of echino-candins in neonates. There are concerns with echinocandins be-cause concentrations in the CNS and in the urinary tract are low.

Dosing of antifungal agents is substantially different for ne-onates than it is for older children and adults. Limited pharma-cokinetic data exist regarding dosing of AmB deoxycholate inneonates, and the pharmacokinetics appear to be highly vari-able in this population [96, 97, 101]. The recommended doseof 1 mg/kg daily results in higher estimates of clearance in in-fants compared with older children and may partially explainwhy the drug is better tolerated in neonates [98]. The durationof therapy is based primarily on adult and pediatric data, andthere are no data to guide duration specifically in neonates.

Population pharmacokinetic studies have provided dosing in-formation for fluconazole in the neonatal population [105, 292].Based on these studies, fluconazole, 12/mg/kg daily, can be usedto treat neonatal candidiasis. More recent data suggest that aloading dose of fluconazole of 25 mg/kg achieves the therapeu-tic target more rapidly than traditional dosing [292]. However,further studies of this dosing scheme are required before it canbe recommended. Failure to promptly remove or replace CVCsin infants with candidemia places the infant at increased risk ofprolonged infection, mortality, and long-term irreversible neu-rodevelopmental impairment [198, 279]. Removal and replace-ment of the catheter at an anatomically distinct site should beperformed unless contraindicated.

What Is the Treatment for Central Nervous System Infectionsin Neonates?

Recommendations

45. For initial treatment, AmB deoxycholate, 1 mg/kg intrave-nous daily, is recommended (strong recommendation; low-quality evidence).


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46. An alternative regimen is liposomal AmB, 5 mg/kg daily(strong recommendation; low-quality evidence).

47. The addition of flucytosine, 25 mg/kg 4 times daily, may beconsidered as salvage therapy in patients who have not had aclinical response to initial AmB therapy, but adverse effectsare frequent (weak recommendation; low-quality evidence).

48. For step-down treatment after the patient has responded toinitial treatment, fluconazole, 12 mg/kg daily, is recommend-ed for isolates that are susceptible to fluconazole (strong rec-ommendation; low-quality evidence).

49. Therapy should continue until all signs, symptoms, andCSF and radiological abnormalities, if present, have resolved(strong recommendation; low-quality evidence).

50. Infected CNS devices, including ventriculostomy drainsand shunts, should be removed if at all possible (strong rec-ommendation; low-quality evidence).

Evidence Summary

There are limited data to guide therapy for CNS Candida infec-tions in the neonate. All AmB preparations, including the lipidformulations, penetrate the CNS and have fungicidal activity inthe CNS [44]. AmB deoxycholate and liposomal AmB werefound to have greater antifungal efficacy when studied in a rab-bit model of Candida meningoencephalitis compared with theother formulations [44]. The clinician must weigh the benefitsand drawbacks of using liposomal AmB with its good CSF pen-etration but poor urine levels vs using AmB deoxycholate withless good CSF levels but better urine levels.

The benefit of adding flucytosine for neonates with CNS can-didiasis is uncertain. In the largest prospective study evaluatingtreatment outcomes of CNS candidiasis in neonates, the mediantime to clear CSF was longer for those who received flucytosineplus AmB deoxycholate (17.5 days; 6 infants), compared withthose who received only AmB deoxycholate (6 days; 18 infants)[279]. In addition, flucytosine is poorly tolerated, and gastroin-testinal side effects may hinder oral feeding in neonates. In ge-neral, flucytosine is used only in neonates who have notresponded to AmB alone.

Data supporting the use of echinocandins in neonates areemerging; however, several key issues require further clarifica-tion. The optimal dose of echinocandins in neonates remainsuncertain [109, 284, 293–297]. Furthermore, there are concernsregarding the penetration of echinocandins into the CSF. Echi-nocandins appear to penetrate brain tissue, but not the CSF, andachieve concentrations in brain shown to be effective in animalmodels when dosages higher than those recommended for hu-mans have been used [298, 299]. Limited clinical data suggestthat the echinocandins may be effective for the treatment ofCNS infections in neonates, but are not adequate to recommendtheir use at this time [293].

What Are the Recommendations for Prophylaxis in the Neo-natal Intensive Care Unit Setting?

Recommendations

51. In nurseries with high rates (>10%) of invasive candidia-sis, intravenous or oral fluconazole prophylaxis, 3–6 mg/kgtwice weekly for 6 weeks, in neonates with birth weights<1000 g is recommended (strong recommendation; high-quality evidence).

52. Oral nystatin, 100 000 units 3 times daily for 6 weeks, is analternative to fluconazole in neonates with birth weights<1500 g in situations in which availability or resistance pre-clude the use of fluconazole (weak recommendation; moder-ate-quality evidence).

53. Oral bovine lactoferrin (100 mg/day) may be effective inneonates <1500 g but is not currently available in US hospi-tals (weak recommendation; moderate-quality evidence).

Evidence Summary

Numerous studies examining fluconazole prophylaxis for theprevention of invasive candidiasis in neonates have consistent-ly demonstrated efficacy and possibly reduced mortality [300–310]. Fluconazole, 3 mg/kg or 6 mg/kg twice weekly, signifi-cantly reduced rates of invasive candidiasis in prematureneonates weighing <1000 g in nurseries with a very high inci-dence of Candida infections [300, 302]. A 2007 Cochranereview of clinical trials of fluconazole prophylaxis demonstrat-ed efficacy, with a typical relative risk of 0.23 and numberneeded to treat of 9. The number needed to treat varied sub-stantially depending on the incidence of invasive candidiasisin a particular ICU. The majority of studies have demonstratedthe safety of fluconazole prophylaxis and lack of emergence ofresistance.

Enteral or orally administered nystatin has been shown to beeffective in reducing invasive candidiasis in preterm infants[303, 311–313]. In one study, nystatin prophylaxis was also as-sociated with a reduction in all-cause mortality [313]. However,there remains a paucity of data on nystatin prophylaxis in in-fants <750 grams (the group at highest risk), and nystatinmay not always be able to be administered when there is anileus, gastrointestinal disease, feeding intolerance, or hemody-namic instability. These clinical situations are very commonin low-gestational-age premature infants and limit the broadapplicability of nystatin prophylaxis as a preventive strategy.

Lactoferrin is a mammalian milk glycoprotein involved in in-nate immunity. In a randomized trial of bovine lactoferrin ininfants <1500 g, the incidence of late-onset sepsis was signifi-cantly lower in the lactoferrin group than in the placebogroup [314]. A secondary analysis of the clinical trial showedthat lactoferrin also reduced the incidence of invasive fungal in-fections compared with placebo [314]. Further confirmation ofthe efficacy and safety of oral bovine lactoferrin for the preven-tion of invasive candidiasis is needed, especially in infants <750g, because there were only a few neonates in this category in thistrial.


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VIII. What Is the Treatment for Intra-abdominal Candidiasis?Recommendations

54. Empiric antifungal therapy should be considered for pa-tients with clinical evidence of intra-abdominal infectionand significant risk factors for candidiasis, including recentabdominal surgery, anastomotic leaks, or necrotizing pancre-atitis (strong recommendation; moderate-quality evidence).

55. Treatment of intra-abdominal candidiasis should includesource control, with appropriate drainage and/or debride-ment (strong recommendation; moderate-quality evidence).

56. The choice of antifungal therapy is the same as for thetreatment of candidemia or empiric therapy for nonneutro-penic patients in the ICU (See sections I and V) (strong rec-ommendation; moderate-quality evidence).

57. The duration of therapy should be determined by adequacyof source control and clinical response (strong recommenda-tion; low-quality evidence).

Evidence Summary

Intra-abdominal candidiasis in patients who have had recentabdominal surgery or intra-abdominal events refers to a hetero-geneous group of infections that includes peritonitis, abdominalabscess, and purulent or necrotic infection at sites of gastroin-testinal perforation or anastomotic leak. Up to 40% of patientswith secondary or tertiary peritonitis, as defined by a multina-tional consensus panel, may develop intra-abdominal candidi-asis with a high mortality rate [243, 244, 315, 316]. A subset ofpostsurgical patients, particularly those with recurrent gastro-duodenal perforation, anastomotic leaks, or acute necrotizingpancreatitis, are at uniquely high risk for invasive candidiasis[243, 244, 263, 316–320]. In other settings, such as perforatedappendicitis, invasive candidiasis appears to be a rare complica-tion [316, 319]. Infections are often polymicrobial, with yeastnoted in as high as 20% of all cases and 40% in patients witha recent gastroduodenal perforation [319, 320].

Diagnosis is hampered by the lack of specific clinical signs andsymptoms. Blood cultures are often negative [321]. A laboratoryreport of yeast isolated from an abdominal specimen must beevaluated to distinguish between contamination, colonization,and invasive infection. Swabs of superficial wounds and speci-mens taken from intra-abdominal catheters that have been inplace for >24 hours do not provide useful information andshould not be performed. In contrast, the presence of yeast ob-tained from normally sterile intra-abdominal specimens (opera-tive room specimens, and/or drains that have been placed within24 hours) in patients with clinical evidence for infection shouldbe considered indicative of intra-abdominal candidiasis.

The role of surrogate markers and Candida risk scores in thissetting has not been established. There are limited data on theutility of using β-D-glucan in postsurgical patients with suspect-ed intra-abdominal candidiasis. In one study, β-D-glucan had a72% positive predictive value and an 80% negative predictive

value for distinguishing colonization from intra-abdominal in-vasive candidiasis and performed better than Candida coloniza-tion scores or indices [143].

Clinical evidence for the use of antifungal therapy for pa-tients with suspected intra-abdominal invasive candidiasis islimited. Most studies are small, uncontrolled, single-center, orperformed in specific populations. Patients who have Candidaspecies isolated from normally sterile abdominal cultures ordrains placed within 24 hours and who have clinical evidenceof infection should be treated for intra-abdominal candidiasis.Patients who have had gastroduodenal perforations, anastomot-ic leaks, necrotizing pancreatitis, or other intra-abdominalevents without the isolation of Candida species and who aredoing poorly despite treatment for bacterial infections may ben-efit from empiric antifungal therapy. Several meta-analyses ofantifungal prophylaxis in high-risk surgical ICU patients haveyielded conflicting results [265–268].

Source control with adequate drainage and/or debridement isan important part of therapy of intra-abdominal candidiasis[14]. The choice of antifungal agent should be guided by theCandida species isolated and knowledge of the local epidemiol-ogy, including antifungal susceptibility patterns. Duration ofantifungal therapy should be guided by clinical response andthe adequacy of source control.

IX. Does the Isolation of Candida Species From the Respiratory TractRequire Antifungal Therapy?Recommendation

58. Growth of Candida from respiratory secretions usuallyindicates colonization and rarely requires treatment with anti-fungal therapy (strong recommendation; moderate-qualityevidence).

Evidence Summary

The isolation of Candida species from the respiratory tract iscommonly encountered among patients who are in the ICUand are intubated or have a chronic tracheostomy. This almostalways reflects colonization of the airways and not infection.Candida pneumonia and lung abscess are very uncommon[322, 323]. Only rarely after aspiration of oropharyngeal mate-rial has primary Candida pneumonia or abscess been docu-mented [324, 325]. Pneumonia due to Candida species isgenerally limited to severely immunocompromised patientswho develop infection following hematogenous spread to thelungs. CT scan of the thorax usually shows multiple pulmonarynodules. Isolation of Candida species from respiratory samplesin a patient who is severely immunosuppressed should trigger asearch for evidence of invasive candidiasis.

Although the diagnosis of Candida pneumonia is supportedby isolation of the organism from a bronchoalveolar lavage(BAL) specimen, a firm diagnosis requires histopathological evi-dence of invasive disease. Multiple prospective and retrospectiveautopsy studies consistently demonstrate the poor predictive


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value of the growth of Candida from respiratory secretions, in-cluding BAL fluid [326–328]. In one prospective study, none of77 patients who died in an ICU and who had clinical and radio-logic evidence of pneumonia and a positive culture for Candidaspecies from BAL or sputum demonstrated evidence of Candidapneumonia at autopsy [328]. Because of the rarity of Candidapneumonia, the extremely common finding of Candida in respi-ratory secretions, and the lack of specificity of this finding [329–331], a decision to initiate antifungal therapy should not be madeon the basis of respiratory tract culture results alone.

Recent observations suggest that colonization of the airwaywith Candida species is associated with the development of bac-terial colonization and pneumonia [332–336]. Candida airwaycolonization was also associated with worse clinical outcomesand higher mortality in these studies. However, it is not clearif Candida airway colonization has a causal relationship topoorer outcomes or is simply a marker of disease severity.

X. What Is the Treatment for Candida Intravascular Infections, IncludingEndocarditis and Infections of Implantable Cardiac Devices?What Is the Treatment for Candida Endocarditis?

Recommendations

59. For native valve endocarditis, lipid formulation AmB, 3–5mg/kg daily, with or without flucytosine, 25 mg/kg 4 timesdaily, OR high-dose echinocandin (caspofungin 150 mg daily,micafungin 150 mg daily, or anidulafungin 200 mg daily) isrecommended for initial therapy (strong recommendation;low-quality evidence).

60. Step-down therapy to fluconazole, 400–800 mg (6–12 mg/kg) daily, is recommended for patients who have flucona-zole-susceptible Candida isolates, have demonstrated clinicalstability, and have cleared Candida from the bloodstream(strong recommendation; low-quality evidence).

61. Oral voriconazole, 200–300 mg (3–4 mg/kg) twice daily, orposaconazole tablets, 300 mg daily, can be used as step-downtherapy for isolates that are susceptible to those agents butnot susceptible to fluconazole (weak recommendation; verylow-quality evidence).

62. Valve replacement is recommended; treatment should con-tinue for at least 6 weeks after surgery and for a longer durationin patients with perivalvular abscesses and other complications(strong recommendation; low-quality evidence).

63. For patients who cannot undergo valve replacement, long-term suppression with fluconazole, 400–800 mg (6–12 mg/kg) daily, if the isolate is susceptible, is recommended (strongrecommendation; low-quality evidence).

64. For prosthetic valve endocarditis, the same antifungal reg-imens suggested for native valve endocarditis are recom-mended (strong recommendation; low-quality evidence).Chronic suppressive antifungal therapy with fluconazole,400–800 mg (6–12 mg/kg) daily, is recommended to preventrecurrence (strong recommendation; low-quality evidence).

Evidence Summary

The incidence of Candida endocarditis has increased concurrentwith the general increase in Candida infections [337]. Endocardi-tis should be suspected when blood cultures are persistently pos-itive, when a patient with candidemia has persistent fever despiteappropriate treatment, or when a new heart murmur, heart fail-ure, or embolic phenomena occur in the setting of candidemia[338]. Most cases occur following cardiac valvular surgery, butother risk factors include injection drug use, cancer chemothera-py, prolonged presence of CVCs, and prior bacterial endocarditis.The signs, symptoms, and complications are generally similar tothose of bacterial endocarditis, except for the frequent occurrenceof large emboli to major vessels. Cases are fairly evenly dividedbetween C. albicans and non-albicans Candida species [339].

Medical therapy of Candida endocarditis has occasionallybeen curative [340–348], but the optimum therapy for both na-tive and prosthetic valve endocarditis in adults is a combinationof valve replacement and a long course of antifungal therapybased on case reports, case series, cohort studies, a meta-analysis, and clinical experience [339, 349]. Valve repair and ve-getectomy are alternatives to valve replacement. Most of thecases reported in the literature have been treated with AmB de-oxycholate, with or without flucytosine [339, 342, 349–355].Fluconazole monotherapy is associated with an unacceptablyhigh rate of relapse and mortality [354]. However, fluconazoleis useful for step-down therapy.

AmB deoxycholate and azoles have decreased activity whencompared with echinocandins against biofilms formed by Candi-da in vitro, and they penetrate poorly into vegetations. Echinocan-dins and lipid formulations of AmB demonstrate more potentactivity against Candida biofilms [356]. A prospective, open-label clinical trial, cohort studies, and several case reports showa role for the echinocandins in the treatment of endocarditis[228, 346, 348, 357–365]. Higher dosages of the echinocandinsare thought to be necessary to treat endocarditis [228, 365]. Cas-pofungin has been used as monotherapy and in combination withAmB, azoles, or flucytosine in single case reports, but data are lim-ited for the other echinocandins [346, 360, 361, 363, 365, 366].

Lifelong suppressive therapy with fluconazole has been usedsuccessfully after a course of primary therapy in patients forwhom cardiac surgery is contraindicated; it has also been advo-cated to prevent late recurrence of Candida prosthetic valve en-docarditis [360, 367, 368]. Because Candida endocarditis has apropensity to relapse months to years later, follow-up should bemaintained for several years after treatment [350, 351].

What Is the Treatment for Candida Infection of ImplantableCardiac Devices?

Recommendations

65. For pacemaker and implantable cardiac defibrillator infec-tions, the entire device should be removed (strong recommen-dation; moderate-quality evidence).


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66. Antifungal therapy is the same as that recommended fornative valve endocarditis (strong recommendation; low-quality evidence).

67. For infections limited to generator pockets, 4 weeks of an-tifungal therapy after removal of the device is recommended(strong recommendation; low-quality evidence).

68. For infections involving the wires, at least 6 weeks of anti-fungal therapy after wire removal is recommended (strongrecommendation; low-quality evidence).

69. For ventricular assist devices that cannot be removed, theantifungal regimen is the same as that recommended for na-tive valve endocarditis (strong recommendation; low-qualityevidence). Chronic suppressive therapy with fluconazole, ifthe isolate is susceptible, for as long as the device remains inplace is recommended (strong recommendation; low-qualityevidence).

Evidence Summary

There are a few case reports and a single retrospective review ofCandida infections of pacemakers and cardiac defibrillators[369–374]. The entire device should be removed and antifungaltherapy given for 4–6 weeks depending on whether the infec-tion involves the wires in addition to the generator pocket[369, 371–374]. Medical therapy alone has failed [370].

There are isolated case reports and a few case series on Can-dida infections of ventricular assist devices [375–378]. The Ex-pert Panel believes that suppressive azole therapy after a fullcourse of initial antifungal therapy is warranted. Many ofthese devices cannot be removed and suppression will be life-long. The role of antifungal prophylaxis to prevent infectionin all patients receiving an assist device remains controversial[378].

What Is the Treatment for Candida SuppurativeThrombophlebitis?

Recommendations

70. Catheter removal and incision and drainage or resection ofthe vein, if feasible, is recommended (strong recommenda-tion; low-quality evidence).

71. Lipid formulation AmB, 3–5 mg/kg daily, OR fluconazole,400–800 mg (6–12 mg/kg) daily, OR an echinocandin (cas-pofungin 150 mg daily, micafungin 150 mg daily, or anidu-lafungin 200 mg daily) for at least 2 weeks after candidemia(if present) has cleared is recommended (strong recommen-dation; low-quality evidence).

72. Step-down therapy to fluconazole, 400–800 mg (6–12 mg/kg) daily, should be considered for patients who have initiallyresponded to AmB or an echinocandin, are clinically stable,and have a fluconazole-susceptible isolate (strong recommen-dation; low-quality evidence).

73. Resolution of the thrombus can be used as evidence to dis-continue antifungal therapy if clinical and culture data aresupportive (strong recommendation; low-quality evidence).

Evidence Summary

Most experience treating suppurative thrombophlebitis hasbeen with AmB deoxycholate. Fluconazole and caspofunginhave also been successful in some cases [379–381], but otheragents used for primary treatment of candidemia, includingechinocandins and voriconazole, should be effective [382].Higher-than-usual doses of echinocandins should be used, sim-ilar to therapy for endocarditis.

Surgical excision of the vein plays an important role in thetreatment of peripheral-vein Candida thrombophlebitis. Whena central vein is involved, surgery is usually not an option. Insome cases, systemic anticoagulation or thrombolytic therapyhas been used as adjunctive therapy, but there are insufficientdata to recommend their use. Thrombolytic therapy, in con-junction with antifungal therapy, has been used successfullyin the management of an infected thrombus attached to aCVC in a patient with persistent candidemia [381].

XI. What Is the Treatment for Candida Osteoarticular Infections?What Is the Treatment for Candida Osteomyelitis?

Recommendations

74. Fluconazole, 400 mg (6 mg/kg) daily, for 6–12 months ORan echinocandin (caspofungin 50–70 mg daily, micafungin100 mg daily, or anidulafungin 100 mg daily) for at least 2weeks followed by fluconazole, 400 mg (6 mg/kg) daily, for6–12 months is recommended (strong recommendation;low-quality evidence).

75. Lipid formulation AmB, 3–5 mg/kg daily, for at least 2weeks followed by fluconazole, 400 mg (6 mg/kg) daily, for6–12 months is a less attractive alternative (weak recommen-dation; low-quality evidence).

76. Surgical debridement is recommended in selected cases(strong recommendation; low-quality evidence).

Evidence Summary

Most patients with osteomyelitis present with a subacute tochronic course [383, 384]. The most common mechanism of in-fection is hematogenous dissemination, but direct inoculationand contiguous spread of infection also occur. Involvement of2 or more bones is common, and therefore, when a single focusof infection is identified, there should be a search for other sitesof involvement. The axial skeleton, especially the spine, is themost common site of involvement in adults; in children, thelong bones are more commonly involved [228, 384–388]. Nei-ther the clinical picture nor the findings on radiographic imag-ing are specific for Candida infection. Candida albicans remainsthe dominant pathogen. However, 2 retrospective reviews of alarge number of cases found that non-albicans Candida werean increasingly frequent cause of Candida osteomyelitis andmixed infections with bacteria, especially Staphylococcus aure-us, were not uncommon, underscoring the need for biopsy andculture [384, 389].


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Treatment recommendations are based on case reports andcase series. Historically, AmB deoxycholate has been the mostcommonly used agent [388]. Recent literature favors the useof fluconazole or an echinocandin over AmB [228, 384–386].Fluconazole has been used successfully as initial therapyfor patients who have susceptible isolates, but treatmentfailures have also been reported [390–393]. There are casereports of the successful treatment of osteomyelitis withitraconazole, voriconazole, posaconazole, and caspofungin[228, 229, 394–396].

Cure rates appear to be significantly higher when an antifun-gal agent is administered for at least 6 months [384, 385]. Theaddition of AmB deoxycholate or fluconazole to bone cementhas been suggested to be of value as adjunctive therapy in com-plicated cases and appears to be safe, but this practice is contro-versial [397, 398].

Surgical debridement is frequently performed in conjunctionwith antifungal therapy. Some reports have found surgical ther-apy important for Candida vertebral osteomyelitis [387], butothers have not found that to be the case [388]. Surgery is indi-cated in patients who have neurological deficits, spinal instabil-ity, large abscesses, or persistent or worsening symptoms duringtherapy [384].

On the basis of a small number of cases, Candida mediasti-nitis and sternal osteomyelitis in patients who have undergonesternotomy can be treated successfully with surgical debride-ment followed by either AmB or fluconazole [391, 399]. Irriga-tion of the mediastinal space with AmB is not recommended,because it can cause irritation. Antifungal therapy of severalmonths’ duration, similar to that needed for osteomyelitis atother sites, is appropriate.

What Is the Treatment for Candida Septic Arthritis?

77. Fluconazole, 400 mg (6 mg/kg) daily, for 6 weeks OR anechinocandin (caspofungin 50–70 mg daily, micafungin100 mg daily, or anidulafungin 100 mg daily) for 2 weeksfollowed by fluconazole, 400 mg (6 mg/kg) daily, for at least4 weeks is recommended (strong recommendation; low-quality evidence).

78. Lipid formulation AmB, 3–5 mg/kg daily, for 2 weeks, fol-lowed by fluconazole, 400 mg (6 mg/kg) daily, for at least 4weeks is a less attractive alternative (weak recommendation;low-quality evidence).

79. Surgical drainage is indicated in all cases of septic arthritis(strong recommendation; moderate-quality evidence).

80. For septic arthritis involving a prosthetic device, device re-moval is recommended (strong recommendation; moderate-quality evidence).

81. If the prosthetic device cannot be removed, chronic sup-pression with fluconazole, 400 mg (6 mg/kg) daily, if the iso-late is susceptible, is recommended (strong recommendation;low-quality evidence).

Evidence Summary

Adequate drainage is critical to successful therapy of Candida ar-thritis. In particular, Candida arthritis of the hip requires opensurgical drainage. Case reports have documented cures withAmB, fluconazole, and caspofungin therapy in combinationwith adequate drainage [400–402]. Administration of eitherAmB or fluconazole produces substantial synovial fluid levels, sothat intra-articular injection of antifungal agents is not necessary.

Candida prosthetic joint infection generally requires resec-tion arthroplasty, although success with medical therapy alonehas been described rarely [403, 404]. The combination of re-moval and reimplantation of the prosthesis in 2 stages separatedby 3–6 months and a prolonged period of antifungal therapy forat least 12 weeks after the resection arthroplasty and at least 6weeks after prosthesis implantation is suggested on the basisof limited data [405–407]. The efficacy of antifungal-loaded ce-ment spacers is controversial [408]. If the prosthetic device can-not be removed, chronic suppression with an antifungal agent,usually fluconazole, is necessary.

XII. What Is the Treatment for Candida Endophthalmitis?What Is the General Approach to Candida Endophthalmitis?

Recommendations

82. All patients with candidemia should have a dilated retinalexamination, preferably performed by an ophthalmologist,within the first week of therapy in nonneutropenic patientsto establish if endophthalmitis is present (strong recommen-dation; low-quality evidence). For neutropenic patients, it isrecommended to delay the examination until neutrophil re-covery (strong recommendation; low-quality evidence).

83. The extent of ocular infection (chorioretinitis with or with-out macular involvement and with or without vitritis) shouldbe determined by an ophthalmologist (strong recommenda-tion; low-quality evidence).

84. Decisions regarding antifungal treatment and surgical in-tervention should be made jointly by an ophthalmologist andan infectious diseases physician (strong recommendation;low-quality evidence).

Evidence Summary

Endophthalmitis refers to infections within the eye, usually in-volving the posterior chamber and sometimes also the anteriorchamber. Candida endophthalmitis can be exogenous, initiallyaffecting the anterior chamber and occurring following traumaor a surgical procedure. More often, Candida species cause en-dogenous infection in which the organism reaches the posteriorchamber of the eye via hematogenous spread. Endogenous in-fections can be manifested as isolated chorioretinitis or as cho-rioretinitis with extension into the vitreous, leading to vitritis[409–412]. Candida albicans is the species most commonly re-sponsible for endogenous endophthalmitis, but all Candidaspecies that cause candidemia have been reported to cause


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this complication [411–414].Outcomes in terms of visual acuitydepend on the extent of visual loss at the time of presentationand macular involvement [415].

Several basic principles are important in the approach to treat-ment of Candida infections of the eye. It should first be deter-mined whether infection involves the anterior and/or posteriorsegment of the eye and whether the macula or vitreous are in-volved [70, 416–418]. Achieving adequate concentrations of theappropriate antifungal agent in the area of the eye that is infectedis crucial to success [419, 420]. Infections involving the chorior-etinal layer are more easily treated because this area of the poste-rior chamber is highly vascular; many systemic antifungal agentslikely reach adequate concentrations within the choroid and theretina [420–422]. The antifungal susceptibilities of the infectingspecies are important. Species that are susceptible to fluconazoleor voriconazole are more easily treated because these agentsachieve adequate concentrations in the posterior segment ofthe eye, including the vitreous [419, 420, 422]. Treatment mustbe systemic to treat candidemia and other organ involvement,if present, in addition to the ocular infection.

Sight-threatening lesions near the macula or invasion into thevitreous usually necessitate intravitreal injection of antifungalagents, usually AmB deoxycholate or voriconazole, with or with-out vitrectomy, in addition to systemic antifungal agents [412,419, 422–425]. The ophthalmologist plays a key role in followingthe course of endogenous Candida endophthalmitis, decidingwhen and if to perform intravitreal injections and vitrectomy.

The approach to the patient who has candidemia hasevolved over time, and standard practice now includes consul-tation with an ophthalmologist to do a dilated retinal exami-nation. The basis for the recommendation to perform anophthalmological evaluation is not a result of randomizedcontrolled trials showing the benefits of such an assessment,but rather clinical judgment that the result of missing andnot appropriately treating Candida endophthalmitis couldbe of great consequence to the patient. The issue of whetheran ophthalmological examination of all candidemic patientsis cost-effective has been raised [183, 426]. The members ofthe Expert Panel believe that the risk of missing Candida en-dophthalmitis outweighs the cost of obtaining an ophthalmo-logical examination. We are concerned about the greater riskof loss of visual acuity in patients who are examined only aftermanifesting ocular symptoms [415], and note that other cen-ters report higher rates of endophthalmitis than reports fromthe centers cited by those who question the routine use of oc-ular examination [417, 418, 421].

What Is the Treatment for Candida Chorioretinitis WithoutVitritis?

Recommendations

85. For fluconazole-/voriconazole-susceptible isolates, flucon-azole, loading dose, 800 mg (12 mg/kg), then 400–800 mg

(6–12 mg/kg) daily OR voriconazole, loading dose 400 mg(6 mg/kg) intravenous twice daily for 2 doses, then 300 mg(4 mg/kg) intravenous or oral twice daily is recommended(strong recommendation; low-quality evidence).

86. For fluconazole-/voriconazole-resistant isolates, liposomalAmB, 3–5 mg/kg intravenous daily, with or without oral flu-cytosine, 25 mg/kg 4 times daily is recommended (strong rec-ommendation; low-quality evidence).

87. With macular involvement, antifungal agents as notedabove PLUS intravitreal injection of either AmB deoxycho-late, 5–10 µg/0.1 mL sterile water, or voriconazole, 100 µg/0.1 mL sterile water or normal saline, to ensure a prompthigh level of antifungal activity is recommended (strong rec-ommendation; low-quality evidence).

88. The duration of treatment should be at least 4–6 weeks,with the final duration depending on resolution ofthe lesions as determined by repeated ophthalmological ex-aminations (strong recommendation; low-quality evidence).

Evidence Summary

The greatest clinical experience for treatment of Candida en-dophthalmitis has been with intravenous AmB deoxycholate,only because it has been available for the longest time. However,this agent does not achieve adequate concentrations in the pos-terior chamber [419, 420, 427, 428]. In animal experiments ininflamed eyes, liposomal AmB achieved higher concentrationsin the eye than either AmB deoxycholate or AmB lipid complex[427]. A few patients have been treated successfully with lipidformulations of AmB, but concentrations in the vitreous in hu-mans have not been reported [429].

Flucytosine provides adjunctive synergistic activity whenused with AmB; it should not be used as monotherapy becauseof development of resistance and reports of decreased efficacy inanimal models [428]. It attains excellent levels in the ocularcompartments, including the vitreous [412, 430]. Toxicity iscommon, and flucytosine serum levels must be monitoredweekly to prevent dose-related toxicity.

Fluconazole is frequently used for the treatment of Candidaendophthalmitis. In experimental animals, this agent achievesexcellent concentrations throughout the eye, including the vit-reous [428]. In humans, concentrations in the vitreous are ap-proximately 70% of those in the serum [57]. Clinical andmicrobiological response rates in animals with experimental in-fection are somewhat conflicting, with most reports showing ef-ficacy of fluconazole, but some noting better efficacy with AmBthan fluconazole [428, 431, 432]. Early reports in humans notedthe efficacy of fluconazole, but some patients had received intra-vitreal injection of antifungal agents, as well as systemic flucon-azole [433, 434]. Despite the fact that no large published serieshas defined the efficacy of fluconazole therapy, this agent is rou-tinely used for the treatment of Candida endophthalmitis [410,411, 415, 421].


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Voriconazole has played an increasing role in the treatmentof endophthalmitis [419]. Concentrations in the vitreous in hu-mans are approximately 40% of serum concentrations; the drugis relatively safe, and, like fluconazole, can be given by the oralor intravenous route [435–438]. It is more active than flucona-zole against C. glabrata, although resistance is increasing andmay preclude its use for some patients; it is uniformly activeagainst C. krusei. Efficacy of voriconazole in treating Candidaendophthalmitis has been documented, but not comparedwith fluconazole [429, 436, 438]. Serum and (presumably) intra-ocular concentrations of voriconazole are quite variable, andserum trough levels should be routinely monitored to achieveconcentrations between 2 µg/mL and 5 µg/mL to enhance effi-cacy and avoid toxicity [118].

There are few data regarding the use of posaconazole forCandida endophthalmitis. Intraocular penetration is poor,this agent has been used in very few patients, and it is not ap-proved for the treatment of candidemia [419].

Echinocandins are first-line agents for the treatment of can-didemia. Whether they can effectively treat chorioretinitis with-out vitreal involvement cannot be answered with the dataavailable. Penetration of all echinocandins into the differentchambers of the eye is poor, and is especially poor in the vitre-ous [412, 419, 420]. When levels have been achieved in experi-mental animal models and in one study in humans withmicafungin, the dosages needed have been higher than thosecurrently licensed for use [112, 439–443]. Only a few case re-ports of the use of an echinocandin as monotherapy havebeen published, and the results are contradictory [444, 445].With the availability of other agents that achieve adequate con-centrations in the vitreous, there is little reason to recommendthe use of echinocandins for Candida endophthalmitis.

Because involvement of the macula is sight-threatening andconcentrations of antifungal agents in the posterior chamber donot immediately reach therapeutic levels, many ophthalmologistsperform an intravitreal injection of either AmB deoxycholate orvoriconazole to quickly achieve high antifungal activity in the pos-terior chamber. AmB is the agent that has been used most oftenfor intravitreal injection [422, 423]. A dosage of 5–10 µg given in0.1 mL sterile water is generally safe [419]. Intravitreal injection oflipid formulations of AmB has been compared with AmB deoxy-cholate in rabbits; all formulations showed toxicity at higher doses,but at 10 µg, the least toxic was liposomal AmB [446], confirminga prior study using a noncommercial liposomal formulation [447].

Voriconazole is increasingly used for intravitreal injection forboth Candida and mold endophthalmitis [438, 448]. It has beenshown to be safe in animal eyes at concentrations <250 µg/mL[449]. The usual dose given to humans is 100 µg in 0.1 mL ster-ile water or normal saline (achieving a final concentration of 25µg/mL) [419, 438]. In vitrectomized eyes, the half-life of bothAmB and voriconazole is shortened, and repeated injectionsmay be required [450, 451].

What Is the Treatment for Candida Chorioretinitis WithVitritis?

Recommendations

89. Antifungal therapy as detailed above for chorioretinitiswithout vitritis, PLUS intravitreal injection of either ampho-tericin B deoxycholate, 5–10 µg/0.1 mL sterile water, orvoriconazole, 100 µg/0.1 mL sterile water or normal saline,is recommended (strong recommendation; low-qualityevidence).

90. Vitrectomy should be considered to decrease the burden oforganisms and to allow the removal of fungal abscesses thatare inaccessible to systemic antifungal agents (strong recom-mendation; low-quality evidence).

91. The duration of treatment should be at least 4–6 weeks,with the final duration dependent on resolution of the lesionsas determined by repeated ophthalmological examinations(strong recommendation; low-quality evidence).

Evidence Summary

Candida endophthalmitis that has extended into the vitreousresults in worse visual outcomes than chorioretinitis withoutvitritis [415]. This may be related to the inability of many anti-fungal agents to achieve adequate concentrations in the vitreousbody. Poor outcomes could also be due to an increased burdenof organisms in the posterior chamber or the existence of an ab-scess that cannot be visualized through the vitreal haziness. Ad-ditionally, in cases of endophthalmitis in which fungemia is notdocumented and the organism is unknown, vitrectomy pro-vides material for culture that is superior to needle aspirationand allows the proper antifungal agent to be used [422, 424].

The treatment when vitritis is documented is similar to thatrecommended for chorioretinitis without vitreal involvement,with the added recommendations to (1) inject either AmB de-oxycholate or voriconazole into the vitreous to achieve highdrug concentrations in the posterior chamber and to (2) consid-er performing a pars plana vitrectomy. Several small series havenoted success in patients in whom early pars plana vitrectomywas accomplished [415, 423, 424, 452]. Removal of the vitreousis usually accompanied by intravitreal injection of antifungalagents, and as noted above, the half-life of injected antifungalagents is shortened with vitrectomy [450, 451]. The risk of ret-inal detachment, a severe late complication of endophthalmitiswith vitreal involvement, is decreased with early vitrectomy[412, 415]. To have the best outcomes, Candida endophthalmi-tis with vitritis must be managed with close cooperation be-tween ophthalmologists and infectious diseases specialists.

XIII. What Is the Treatment for Central Nervous System Candidiasis?Recommendations

92. For initial treatment, liposomal AmB, 5 mg/kg daily,with or without oral flucytosine, 25 mg/kg 4 times daily,is recommended (strong recommendation; low-qualityevidence).


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93. For step-down therapy after the patient has responded to ini-tial treatment, fluconazole, 400–800 mg (6–12 mg/kg) daily, isrecommended (strong recommendation; low-quality evidence).

94. Therapy should continue until all signs and symptoms andCSF and radiological abnormalities have resolved (strong rec-ommendation; low-quality evidence).

95. Infected CNS devices, including ventriculostomy drains,shunts, stimulators, prosthetic reconstructive devices, and bio-polymer wafers that deliver chemotherapy, should be removedif possible (strong recommendation; low-quality evidence).

96. For patients in whom a ventricular device cannot be re-moved, AmB deoxycholate could be administered throughthe device into the ventricle at a dosage ranging from 0.01mg to 0.5 mg in 2 mL 5% dextrose in water (weak recommen-dation; low-quality evidence).

Evidence Summary

CNS Candida infections can occur as a manifestation of dissem-inated candidiasis, as a complication of a neurosurgical proce-dure, especially when an intracranial device is inserted, or rarelyas an isolated chronic infection [453–462]. Meningitis is themost common presentation, but multiple small abscessesthroughout the brain parenchyma, large solitary brain abscess-es, and epidural abscesses have been reported [462]. Low-birth-weight neonates are at high risk to have CNS infection as a com-plication of candidemia; neonatal CNS candidiasis is dealt within the section on neonatal Candida infections. Most infectionsare due to C. albicans, with few reports of C. glabrata and otherspecies causing infection [453–457, 459, 461, 462]. Treatment isbased on the antifungal susceptibilities of the infecting speciesand the ability of the antifungal agent to achieve appropriateconcentrations in the CSF and brain.

No randomized controlled trials have been performed to eval-uate the most appropriate treatment for these uncommon infec-tions. Single cases and small series are reported. Most experiencehas accrued with the use of AmB deoxycholate, with or withoutflucytosine [453–455, 457, 459, 460, 462]. Liposomal AmB (Am-Bisome) has been found to attain higher levels in the brain thanamphotericin B lipid complex (ABLC) or AmB deoxycholate in arabbit model of Candida meningoencephalitis [44].

The combination of AmB and flucytosine is recommendedbecause of the in vitro synergism noted with the combinationand the excellent CSF concentrations achieved by flucytosine.However, flucytosine’s toxic effects on bone marrow and livermust be carefully monitored, preferably with frequent serumflucytosine levels. The optimal length of therapy with AmBalone or in combination with flucytosine has not been studied.Several weeks of therapy are suggested before transitioning tooral azole therapy.

Fluconazole achieves excellent levels in CSF and brain tissueand has proved useful as step-down therapy [453, 454, 459]. Flu-conazole also has been used as monotherapy; both success and

failure have been noted, and for this reason it is not recom-mended as first-line therapy [453, 454, 463–465]. Fluconazolecombined with flucytosine has been reported to cure Candidameningitis in a few patients [459], and this is a possible regimenfor step-down therapy. There are no reports of the use of vori-conazole or posaconazole for CNS candidiasis. Voriconazoleachieves excellent levels in CSF, and should be consideredfor the rare case of C. glabrata that is not voriconazoleresistant or C. krusei meningitis after initial treatment withAmB with or without flucytosine. Posaconazole does notreach adequate concentrations in the CSF, and this agent isnot recommended.

Echinocandins have been used infrequently for CNS candidi-asis. There are case reports noting success [466], but CNS break-through infections in patients receiving an echinocandin forcandidemia have been reported [467]. There are experimentalanimal data noting that anidulafungin and micafungin can suc-cessfully treat C. albicans meningitis, but the doses required inhumans are much higher than currently recommended for can-didemia [296, 299]. At present, echinocandins are not recom-mended for CNS candidiasis.

Infected CNS devices should be removed to eradicate Candi-da. Most experience has been with external ventricular drainsand ventriculoperitoneal shunts that have become infectedwith Candida species [460, 463]. In recent years, infected devic-es include deep brain stimulators and Gliadel biopolymer wa-fers that have been placed into the site of a brain tumor todeliver chemotherapy locally. Although difficult to remove, ex-perience has shown that these devices must be taken out forcure of the infection [456, 468, 469].

Intraventricular administration of antifungal agents is not usu-ally necessary for treatment of CNS Candida infections. In pa-tients in whom the removal of a ventricular shunt or externalventriculostomy drain is too risky because of significantly elevatedintracranial pressure, or among patients who have not respondedto systemic antifungal therapy, intraventricular AmB deoxycholatehas proved useful [453, 454, 460, 463, 469]. The dose of intraven-tricular AmB deoxycholate is not standardized, and recommenda-tions vary from 0.01 mg to 1 mg in 2 mL of 5% dextrose in waterdaily [455, 463, 466, 469]. Toxicity—mainly headache, nausea, andvomiting—is a limiting factor when administering AmB by thisroute [454, 463].

XIV. What Is the Treatment for Urinary Tract Infections Due to CandidaSpecies?What Is the Treatment for Asymptomatic Candiduria?

Recommendations

97. Elimination of predisposing factors, such as indwellingbladder catheters, is recommended whenever feasible (strongrecommendation; low-quality evidence).

98. Treatment with antifungal agents is NOT recommendedunless the patient belongs to a group at high risk for


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dissemination; high-risk patients include neutropenic pa-tients, very low-birth-weight infants (<1500 g), and patientswho will undergo urologic manipulation (strong recommen-dation; low-quality evidence).

99. Neutropenic patients and very low-birth-weight infantsshould be treated as recommended for candidemia (see sec-tions III and VII) (strong recommendation; low-qualityevidence).

100. Patients undergoing urologic procedures should be treatedwith oral fluconazole, 400 mg (6 mg/kg) daily, OR AmB deox-ycholate, 0.3–0.6 mg/kg daily, for several days before and afterthe procedure (strong recommendation; low-quality evidence).

Evidence Summary

The presence of candiduria is the usual trigger for a physician toconsider whether a patient has a urinary tract infection due toCandida species. The patients at most risk for candiduria arethose who are elderly, female, diabetic, have indwelling urinarydevices, are taking antibiotics, and have had prior surgical pro-cedures [470–475]. In the asymptomatic patient, candiduria al-most always represents colonization, and elimination ofunderlying risk factors, such as indwelling catheters, is often ad-equate to eradicate candiduria [471].

Multiple studies have noted that candiduria does not com-monly lead to candidemia [471, 472, 476–480]. Several ofthese studies have shown that candiduria is a marker for greatermortality, but death is not related to Candida infection andtreatment for Candida infection does not change mortalityrates [476, 480, 481]. A prospective study in renal transplant re-cipients found that although mortality was higher in patientswho had candiduria, treatment did not improve outcomes, sug-gesting again that candiduria is a marker for severity of under-lying illness [482].

Several conditions require an aggressive approach to candi-duria in asymptomatic patients. These include neonates withvery low birth weight, who are at risk for invasive candidiasisthat often involves the urinary tract [281, 483]. Many physi-cians who care for neutropenic patients treat those who havefever and candiduria because the candiduria may indicate in-vasive candidiasis. However, a recent study from a cancer hos-pital of a small number of patients, 25% of whom wereneutropenic, found that these patients did not develop candi-demia or other complications of candiduria [484]. Several re-ports have documented a high rate of candidemia whenpatients undergo urinary tract instrumentation [485, 486],which has led to recommendations to treat with antifungalagents periprocedure.

What Is the Treatment for Symptomatic Candida Cystitis?

Recommendations

101. For fluconazole-susceptible organisms, oral fluconazole,200 mg (3 mg/kg) daily for 2 weeks is recommended (strongrecommendation; moderate-quality evidence).

102. For fluconazole-resistant C. glabrata, AmB deoxycholate,0.3–0.6 mg/kg daily for 1–7 days OR oral flucytosine, 25 mg/kg 4 times daily for 7–10 days is recommended (strong rec-ommendation; low-quality evidence).


104. Removal of an indwelling bladder catheter, if feasible, isstrongly recommended (strong recommendation; low-qualityevidence).

105. AmB deoxycholate bladder irrigation, 50 mg/Lsterile water daily for 5 days, may be useful for treatmentof cystitis due to fluconazole-resistant species, such as C.glabrata and C. krusei (weak recommendation; low-qualityevidence).

What Is the Treatment for Symptomatic Ascending CandidaPyelonephritis?

Recommendations

106. For fluconazole-susceptible organisms, oral fluconazole,200–400 mg (3–6 mg/kg) daily for 2 weeks, is recommended(strong recommendation; low-quality evidence).

107. For fluconazole-resistant C. glabrata, AmB deoxycholate,0.3–0.6 mg/kg daily for 1–7 days, with or without oral flucy-tosine, 25 mg/kg 4 times daily, is recommended (strong rec-ommendation; low-quality evidence).

108. For fluconazole-resistant C. glabrata, monotherapy withoral flucytosine, 25 mg/kg 4 times daily for 2 weeks, couldbe considered (weak recommendation; low-quality evidence).


110. Elimination of urinary tract obstruction is strongly rec-ommended (strong recommendation; low-quality evidence).

111. For patients who have nephrostomy tubes or stents inplace, consider removal or replacement, if feasible (weak rec-ommendation; low-quality evidence).

Evidence Summary

Candida UTI can develop by 2 different routes [487]. Mostsymptomatic UTIs evolve as an ascending infection beginningin the lower urinary tract, similar to the pathogenesis of bacte-rial UTI. Patients with ascending infection can have symptomsof cystitis or pyelonephritis. The other route of infection occursas a consequence of hematogenous spread to the kidneys in apatient who has candidemia. These patients usually have no uri-nary tract symptoms or signs, and are treated for candidemia.

Diagnostic tests on urine often are not helpful in differenti-ating colonization from infection or in pinpointing the involvedsite within the urinary tract [488, 489]. For example, pyuria in apatient with an indwelling bladder catheter cannot differentiateCandida infection from colonization. Similarly, the colony


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count in the urine, especially when a catheter is present, cannotbe used to define infection [488, 489]. Imaging of the urinarytract by ultrasound or CT scanning is helpful in defining struc-tural abnormalities, hydronephrosis, abscesses, emphysematouspyelonephritis, and fungus ball formation [490–492]. Aggrega-tion of mycelia and yeasts (fungus balls) in bladder or kidneyleads to obstruction and precludes successful treatment of infec-tion with antifungal agents alone [94]. Rarely, Candida speciescause localized infections in prostate, epididymis, or testicles[491, 493–495].

Several basic principles are important in the approach totreatment of Candida UTI. The ability of the antifungal agentto achieve adequate concentrations in the urine is as importantas the antifungal susceptibilities of the infecting species [94].Candida albicans, the most common cause of fungal UTI, is rel-atively easy to treat because it is susceptible to fluconazole,which achieves high concentrations in the urine. In contrast,UTIs due to fluconazole-resistant C. glabrata and C. kruseican be extremely difficult to treat.

Fluconazole is the drug of choice for treating Candida UTI. Itwas shown to be effective in eradicating candiduria in the onlyrandomized, double-blind, placebo-controlled trial that hasbeen conducted in patients with candiduria [496]. It is impor-tant to note that the patients in this trial were asymptomatic orhad minimal symptoms of cystitis. Fluconazole is available as anoral formulation, is excreted into the urine in its active form,and easily achieves urine levels exceeding the MIC for mostCandida isolates [94].

Flucytosine demonstrates good activity against many Candi-da species, with the exception of C. krusei, and is excreted asactive drug in the urine [94]. Treatment with flucytosine is lim-ited by its toxicity and the development of resistance when it isused as a single agent.

AmB deoxycholate is active against most Candida species (al-though some C. krusei isolates are resistant) and achieves con-centrations in the urine that exceed the MICs for most isolates,and even low doses have been shown to be effective in treatingCandida UTI [497]. The major drawbacks are the need for in-travenous administration and toxicity. The lipid formulations ofAmB appear to not achieve urine concentrations that are ade-quate to treat UTI and should not be used [498].

All other antifungal drugs, including the other azole agentsand echinocandins, have minimal excretion of active druginto the urine and generally are ineffective in treating CandidaUTI [94]. However, there are several reports of patients inwhom echinocandins were used, primarily because of UTIdue to fluconazole-resistant organisms, and both success andfailure were reported [499–502]. Infection localized to the kid-ney, as occurs with hematogenous spread, probably can be treat-ed with echinocandins because tissue concentrations areadequate even though these agents do not achieve adequateurine concentrations [499].

Irrigation of the bladder with AmB deoxycholate resolves can-diduria in 80%–90% of patients, as shown in several open-labeltrials, but in those studies, recurrent candiduria within severalweeks was very common [503–505]. This approach is usefulonly for bladder infections and generally is discouraged, especiallyin patients who would not require an indwelling catheter for anyother reason [94, 506, 507].Cystitis due to C. glabrata or C. kruseican sometimes be treated with amphotericin B bladder irrigationand endoscopic removal of any obstructing lesions [94].

What Is the Treatment for Candida Urinary Tract InfectionAssociated With Fungus Balls?

Recommendations

112. Surgical intervention is strongly recommended in adults(strong recommendation; low-quality evidence).

113. Antifungal treatment as noted above for cystitis or pyelo-nephritis is recommended (strong recommendation; low-quality evidence).

114. Irrigation through nephrostomy tubes, if present, withAmB deoxycholate, 25–50 mg in 200–500 mL sterile water,is recommended (strong recommendation; low-qualityevidence).

Evidence Summary

Fungus balls are an uncommon complication of Candida UTIexcept in neonates, in whom fungus ball formation in the col-lecting system commonly occurs as a manifestation of dissem-inated candidiasis [483]. In adults, surgical or endoscopicremoval of the obstructing mycelial mass is central to successfultreatment [94, 508, 509]. In neonates, some series documentedresolution of fungus balls with antifungal treatment alone [510],but others found that endoscopic removal was necessary [511,512]. There are anecdotal reports of a variety of techniques usedto remove fungus balls from the renal pelvis; these include en-doscopic removal via a percutaneous nephrostomy tube, infu-sion of streptokinase locally, and irrigation with antifungalagents through a nephrostomy tube [511–513]. Fungus ballsin the bladder and lower ureter usually can be removed endo-scopically [509].

XV. What Is the Treatment for Vulvovaginal Candidiasis?Recommendations

115. For the treatment of uncomplicated Candida vulvovagini-tis, topical antifungal agents, with no one agent superior toanother, are recommended (strong recommendation; high-quality evidence).

116. Alternatively, for the treatment of uncomplicated Candi-da vulvovaginitis, a single 150-mg oral dose of fluconazole isrecommended (strong recommendation; high-qualityevidence).

117. For severe acute Candida vulvovaginitis, fluconazole 150mg, given every 72 hours for a total of 2 or 3 doses, is recom-mended (strong recommendation; high-quality evidence).


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118. For C. glabrata vulvovaginitis that is unresponsive to oralazoles, topical intravaginal boric acid, administered in a gel-atin capsule, 600 mg daily, for 14 days is an alternative(strong recommendation; low-quality evidence).

119. Another alternative agent for C. glabrata infection is nys-tatin intravaginal suppositories, 100 000 units daily for 14days (strong recommendation; low-quality evidence).

120. A third option for C. glabrata infection is topical 17% flu-cytosine cream alone or in combination with 3% AmB creamadministered daily for 14 days (weak recommendation; low-quality evidence).

121. For recurring vulvovaginal candidiasis, 10–14 days ofinduction therapy with a topical agent or oral fluconazole, fol-lowed by fluconazole, 150 mg weekly for 6 months, is recom-mended (strong recommendation; high-quality evidence).

Evidence Summary

Vulvovaginal candidiasis can be classified as either uncompli-cated, which is present in about 90% of cases, or complicated,which accounts for only about 10% of cases, on the basis of clin-ical presentation, microbiological findings, host factors, and re-sponse to therapy [514]. Complicated vulvovaginal candidiasisis defined as severe or recurrent disease, infection due to non-albicans species, and/or infection in an abnormal host. Candidaalbicans is the usual pathogen, but other Candida species canalso cause this infection.

A diagnosis of vulvovaginal candidiasis can usually be madeclinically when a woman presents with symptoms of pruritus,irritation, vaginal soreness, external dysuria, and dyspareunia,often accompanied by a change in vaginal discharge. Signs in-clude vulvar edema, erythema, excoriation, fissures, and a white,thick, curdlike vaginal discharge. Unfortunately, these symp-toms and signs are nonspecific and can be the result of a varietyof infectious and noninfectious etiologies. Before proceedingwith empiric antifungal therapy, the diagnosis should be con-firmed by a wet-mount preparation with use of saline and10% potassium hydroxide to demonstrate the presence ofyeast or hyphae and a normal pH (4.0–4.5). For those with neg-ative findings, vaginal cultures for Candida should be obtained.

A variety of topical and systemic oral agents are available fortreatment of vulvovaginal candidiasis. No evidence exists toshow the superiority of any one topical regimen [515, 516],and oral and topical antifungal formulations have been shownto achieve entirely equivalent results [517]. Uncomplicated in-fection can be effectively treated with either single-dose flucon-azole or short-course fluconazole for 3 days, both of whichachieve >90% response [517, 518]. Treatment of vulvovaginalcandidiasis should not differ on the basis of human immunode-ficiency virus (HIV) infection status; identical response rates areanticipated for HIV-positive and HIV-negative women.

Complicated vulvovaginal candidiasis requires that therapybe administered intravaginally with topical agents for 5–7

days or orally with fluconazole 150 mg every 72 hours for 3doses [54, 514]. Most Candida species, with the exception ofC. krusei and C. glabrata, respond to oral fluconazole. Candidakrusei responds to all topical antifungal agents. However, treat-ment of C. glabrata vulvovaginal candidiasis is problematic[514, 516]. The most important decision to make is whetherthe presence of C. glabrata in vaginal cultures reflects coloniza-tion in a patient who has another disease, or whether it indicatestrue infection requiring treatment. Azole therapy, includingvoriconazole, is frequently unsuccessful [519]. A variety oflocal regimens have sometimes proved effective. These includeboric acid contained in gelatin capsules and nystatin intravagi-nal suppositories [520]. Topical 17% flucytosine cream can beused alone or in combination with 3% AmB cream in recalci-trant cases [520, 521]. These topical formulations, as well asboric acid gelatin capsules, must be compounded by a pharmacistfor specific patient use. Azole-resistant C. albicans infections areextremely rare. However, recent evidence has emerged docu-menting fluconazole and azole class resistance in women follow-ing prolonged azole exposure [522].

Recurrent vulvovaginal candidiasis, defined as ≥4 episodes ofsymptomatic infection within one year, is usually caused byazole-susceptible C. albicans [514, 523]. Contributing factors,such as diabetes, are rarely found. Treatment should beginwith induction therapy with a topical agent or oral fluconazolefor 10–14 days, followed by a maintenance azole regimen for atleast 6 months [523–525]. The most convenient and well-tolerated regimen is 150 mg fluconazole once weekly. This reg-imen achieves control of symptoms in >90% of patients [523].After cessation of maintenance therapy, a 40%–50% recurrencerate can be anticipated. If fluconazole therapy is not feasible,topical clotrimazole cream, 200 mg twice weekly, clotrimazolevaginal suppository 500 mg once weekly, or other intermittentoral or topical antifungal treatment is recommended [526, 527].

XVI. What Is the Treatment for Oropharyngeal Candidiasis?Recommendations

122. For mild disease, clotrimazole troches, 10 mg 5 timesdaily, OR miconazole mucoadhesive buccal 50 mg tablet ap-plied to the mucosal surface over the canine fossa once dailyfor 7–14 days, are recommended (strong recommendation;high-quality evidence).

123. Alternatives for mild disease include nystatin suspension(100 000 U/mL) 4–6 mL 4 times daily, OR 1–2 nystatin pas-tilles (200 000 U each) 4 times daily, for 7–14 days (strongrecommendation; moderate-quality evidence).

124. For moderate to severe disease, oral fluconazole, 100–200mg daily, for 7–14 days is recommended (strong recommen-dation; high-quality evidence).

125. For fluconazole-refractory disease, itraconazole solution,200 mg once daily OR posaconazole suspension, 400 mgtwice daily for 3 days then 400 mg daily, for up to 28 days,


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are recommended (strong recommendation; moderate-qualityevidence).

126. Alternatives for fluconazole-refractory disease includevoriconazole, 200 mg twice daily, OR AmB deoxycholateoral suspension, 100 mg/mL 4 times daily (strong recommen-dation; moderate-quality evidence).

127. Intravenous echinocandin (caspofungin: 70-mg loadingdose, then 50 mg daily; micafungin: 100 mg daily; or ani-dulafungin: 200-mg loading dose, then 100 mg daily) OR in-travenous AmB deoxycholate, 0.3 mg/kg daily, are otheralternatives for refractory disease (weak recommendation;moderate-quality evidence).

128. Chronic suppressive therapy is usually unnecessary. If re-quired for patients who have recurrent infection, fluconazole,100 mg 3 times weekly, is recommended (strong recommen-dation; high-quality evidence).


130. For denture-related candidiasis, disinfection of the den-ture, in addition to antifungal therapy, is recommended(strong recommendation; moderate-quality evidence).

Evidence Summary

Oropharyngeal and esophageal candidiasis occur in associationwith HIV infection, diabetes, leukemia and other malignancies,steroid use, radiation therapy, antimicrobial therapy, and den-ture use [528, 529], and their occurrence is recognized as an in-dicator of immune dysfunction. In HIV-infected patients,oropharyngeal candidiasis is most often observed in patientswith CD4 counts <200 cells/µL [528–530]. The advent of effec-tive antiretroviral therapy has led to a dramatic decline in theprevalence of oropharyngeal candidiasis and a marked diminu-tion in cases of refractory disease [531].

Fluconazole or multiazole resistance is predominantly theconsequence of previous repeated and long-term exposure tofluconazole or other azoles [530–533]. Especially in patientswith advanced immunosuppression and low CD4 counts, C. al-bicans resistance has been described, as has gradual emergenceof non-albicans Candida species, particularly C. glabrata, as acause of refractory mucosal candidiasis [532, 533].

Most cases of oropharyngeal candidiasis are caused by C. al-bicans, either alone or in mixed infections. Symptomatic infec-tions caused by C. glabrata, C. dubliniensis, and C. krusei alonehave been described [532–534]. Multiple randomized prospec-tive studies of oropharyngeal candidiasis have been performedinvolving patients with AIDS and patients with cancer. Mostpatients will respond initially to topical therapy [532, 535,536]. In HIV-infected patients, symptomatic relapses occursooner and more frequently with topical therapy than with flu-conazole [535]. In a multicenter randomized study among HIV-infected individuals, 50-mg mucoadhesive buccal tablets of

miconazole applied once daily to the mucosal surface over thecanine fossa were as effective as 10-mg clotrimazole trochesused 5 times daily [537].

Fluconazole tablets and itraconazole solution are superior toketoconazole and itraconazole capsules [538–540]. Local effectsof oral solutions may be as important as the systemic effects.Posaconazole suspension is also as efficacious as fluconazolein patients with AIDS [541]. Posaconazole, 100-mg delayed re-lease tablets, given as 300 mg daily as a single dose, are FDA ap-proved for the prophylaxis of fungal infections in high-riskpatients. The tablets provide a stable bioavailability (approxi-mately 55%), once-daily dosing, and the convenience of lessstringent food requirements for absorption. This formulationhas not been fully evaluated for mucosal candidiasis, but, withfurther study, could replace the oral suspension for this purpose.

Recurrent infections typically occur in patients who have per-sistent immunosuppression, especially those who have AIDSand low CD4 cell counts (<50 cells/µL) [530–533]. Long-termsuppressive therapy with fluconazole has been shown to be ef-fective in the prevention of oropharyngeal candidiasis [53, 542,543]. In a large multicenter study of HIV-infected patients,long-term suppressive therapy with fluconazole was comparedwith the episodic use of fluconazole in response to symptomaticdisease. Continuous suppressive therapy reduced the relapserate more effectively than did intermittent therapy, but was as-sociated with increased in vitro resistance. The frequency of re-fractory disease was the same for both groups [53]. Oral AmBdeoxycholate, nystatin solution, and itraconazole capsules areless effective than fluconazole in preventing oropharyngeal can-didiasis [544, 545].

Fluconazole-refractory infections should be treated initiallywith itraconazole solution; between 64% and 80% of patientswill respond to this therapy [546, 547]. Posaconazole suspensionis efficacious in approximately 75% of patients with refractoryoropharyngeal or esophageal candidiasis [548], and voriconazolealso is efficacious for fluconazole-refractory infections [549]. In-travenous caspofungin, micafungin, and anidulafungin have beenshown to be effective alternatives to azole agents for refractorycandidiasis [24, 87, 88, 550].Oral or intravenous AmB deoxycho-late is also effective in some patients; however, a pharmacist mustcompound the oral formulation [551]. Immunomodulation withadjunctive granulocyte-macrophage colony-stimulating factor orinterferon-γ have been occasionally used in the management ofrefractory oral and esophageal candidiasis [552, 553].

Decreasing rates of oral carriage of Candida species and a re-duced frequency of symptomatic oropharyngeal candidiasis areseen among HIV-infected patients on effective antiretroviraltherapy [554]. Thus, antiretroviral therapy should be usedwhenever possible for HIV-infected patients with oropharyn-geal or esophageal candidiasis.

Chronic mucocutaneous candidiasis is a rare condition thatis characterized by chronic, persistent onychomycosis and/or


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mucocutaneous lesions due to Candida species. Some patientshave a thymoma or autoimmune polyendocrinopathy syn-drome type 1 [555]. Fluconazole should be used as initial ther-apy for candidiasis in these patients. Response to antifungaltherapy may be delayed when there is extensive skin or nail in-volvement. Because of the intrinsic immunodeficiency, mostpatients require chronic suppressive antifungal therapy and fre-quently develop azole-refractory infections [556]. Patients withfluconazole-refractory Candida infections should be treated thesame as patients with AIDS who develop azole refractory infec-tions [528].

XVII. What Is the Treatment for Esophageal Candidiasis?Recommendations

131. Systemic antifungal therapy is always required. A diag-nostic trial of antifungal therapy is appropriate beforeperforming an endoscopic examination (strong recommenda-tion; high-quality evidence).

132. Oral fluconazole, 200–400 mg (3–6 mg/kg) daily, for 14–21 days is recommended (strong recommendation; high-quality evidence).

133. For patients who cannot tolerate oral therapy, intravenousfluconazole, 400 mg (6 mg/kg) daily, OR an echinocandin(micafungin: 150 mg daily; caspofungin: 70-mg loadingdose, then 50 mg daily; or anidulafungin: 200 mg daily) isrecommended (strong recommendation; high-qualityevidence).

134. A less preferred alternative for those who cannot tolerateoral therapy is AmB deoxycholate, 0.3–0.7 mg/kg daily(strong recommendation; moderate-quality evidence).

135. Consider de-escalating to oral therapy with fluconazole200–400 mg (3–6 mg/kg) daily once the patient is able to tol-erate oral intake (strong recommendation; moderate-qualityevidence).

136. For fluconazole-refractory disease, itraconazole solution,200 mg daily, OR voriconazole, 200 mg (3 mg/kg) twicedaily either intravenous or oral, for 14–21 days is recom-mended (strong recommendation; high-quality evidence).

137. Alternatives for fluconazole-refractory disease include anechinocandin (micafungin: 150 mg daily; caspofungin: 70-mg loading dose, then 50 mg daily; or anidulafungin: 200mg daily) for 14–21 days, OR AmB deoxycholate, 0.3–0.7mg/kg daily, for 21 days (strong recommendation; high-qual-ity evidence).

138. Posaconazole suspension, 400 mg twice daily, or extend-ed-release tablets, 300 mg once daily, could be considered forfluconazole-refractory disease (weak recommendation; low-quality evidence).

139. For patients who have recurrent esophagitis, chronic sup-pressive therapy with fluconazole, 100–200 mg 3 times week-ly, is recommended (strong recommendation; high-qualityevidence).


Evidence Summary

Esophageal candidiasis typically occurs at lower CD4 countsthan oropharyngeal disease [528–530]. The advent of effectiveantiretroviral therapy has led to a dramatic decline in the prev-alence of esophageal candidiasis and a marked diminution incases of refractory disease [531]. Most cases of esophagealcandidiasis are caused by C. albicans. However, symptomaticinfections caused by C. glabrata, C. dubliniensis, and C. kruseihave been described [534].

The presence of oropharyngeal candidiasis and dysphagia orodynophagia in an immunocompromised host is frequentlypredictive of esophageal candidiasis, although esophageal can-didiasis can present as odynophagia without concomitant oro-pharyngeal candidiasis. A therapeutic trial with fluconazolefor patients with presumed esophageal candidiasis is a cost-effective alternative to endoscopic examination. In general,most patients with esophageal candidiasis will have improve-ment or resolution of their symptoms within 7 days after theinitiation of antifungal therapy [557].

Fluconazole is superior to ketoconazole, itraconazole cap-sules, and flucytosine, and is comparable to itraconazole solu-tion for the treatment of esophageal candidiasis [558, 559]; upto 80% of patients with fluconazole-refractory infections will re-spond to itraconazole solution [547]. Voriconazole is as effica-cious as fluconazole and has shown success in the treatment offluconazole-refractory mucosal candidiasis [63, 549].

The echinocandins are as effective as fluconazole but are as-sociated with higher relapse rates than those observed with flu-conazole [24, 87, 88, 550]. Thus, higher doses of echinocandinsare recommended for use for esophageal disease than are usedfor candidemia to decrease relapses. Higher doses have beenstudied for micafungin [560]. Fluconazole-refractory disease re-sponds to caspofungin, and it is likely that micafungin and ani-dulafungin are as effective as caspofungin. In patients withadvanced AIDS, recurrent infections are common, and long-term suppressive therapy with fluconazole is effective in de-creasing the recurrence rates [53]. The use of effective antiretro-viral therapy has dramatically decreased the incidence ofesophageal candidiasis in HIV-infected patients.

NotesAcknowledgments. The Expert Panel expresses its gratitude for

thoughtful reviews of an earlier version by Anna Thorner and PranatharthiChandrasekar; and David van Duin as liaison of the IDSA Standards andPractice Guidelines Committee (SPGC). The panel also greatly appreciatesthe work of Charles B. Wessels and Michele Klein Fedyshin of the HealthSciences Library System of the University of Pittsburgh for the developmentand execution of the systematic literature searches for this guideline.Financial support. Support for this guideline was provided by the In-

fectious Diseases Society of America.


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Potential conflicts of interest. The following list is a reflection of whathas been reported to IDSA. To provide thorough transparency, IDSA re-quires full disclosure of all relationships, regardless of relevancy to the guide-line topic. Evaluation of such relationships as potential conflicts of interest(COI) is determined by a review process that includes assessment by theSPGC Chair, the SPGC liaison to the development panel, and the Boardof Directors liaison to the SPGC and, if necessary, the COI Task Force ofthe Board. This assessment of disclosed relationships for possible COIwill be based on the relative weight of the financial relationship (ie, mone-tary amount) and the relevance of the relationship (ie, the degree to whichan association might reasonably be interpreted by an independent observeras related to the topic or recommendation of consideration). The reader ofthese guidelines should be mindful of this when the list of disclosures is re-viewed. For activities outside of the submitted work, P. G. P. served as a con-sultant to Merck, Astellas (past), Gilead, T2 Biosystems, Scynexis, Viamet,IMMY Diagnostics, and Pfizer (past) and has received research grants fromT2 Biosystems, Gilead, Merck, Astellas, Scynexis, and IMMY. For activitiesoutside of the submitted work, C. A. K. has received research grants from VACooperative Studies, Merck, the Centers for Disease Control and Prevention(CDC) and The National Institute on Aging (all past), and has received roy-alties from UpToDate. For activities outside of the submitted work,D. A. has served a consultant to Merck, Astellas, Pfizer, Seachaid, Mayne,Roche, Theravance, Viamet, and Scynexis and has received research grantsfrom Merck, Pfizer, MSG, Actellion, Theravance, Scynexis, and Astellas. Foractivities outside of the submitted work, C. J. C. has consulted forMerck, andreceived research grants from Pfizer, Merck, Astellas, CSL Behring, and T2Diagnostics. For activities outside of the submitted work, K. A. M. has re-ceived research grants from Pfizer, Astellas, Merck, and the National Insti-tutes of Health (NIH) and served as a consultant for Astellas, Chimerix,Cidara, Genentech, Merck, Revolution Medicines, and Theravance. Shehas a licensed patent to MycoMed Technologies. For activities outside ofthe submitted work, L. O.-Z. has served as a consultant to Viracor (past),Novadigm (past), Pfizer (past), Astellas, Cidara, Scynexis, and Merck andhas received research grants from Merck (past), Astellas, Pfizer (past), Im-munetics, Associates of Cape Cod (past), and T2 Biosystems, and has beenon the speakers’ bureau for Merck and Pfizer. For activities outside of thesubmitted work, A. C. R. has received research grants from Merck and T2Biosystems, and royalties from UpToDate. For activities outside of the sub-mitted work, J. A. V. has served as a consultant for Astellas, Forest, served onpromotional speakers’ bureau for Astellas, Pfizer, Forest, and Astra Zeneca,and has received research grants from Astellas, Pfizer, Merck, MSG, T2 Bio-systems, and NIH/National Institute of Dental and Craniofacial Research.For activities outside of the submitted work, T. J. W. has served as a consul-tant for Astellas, Drais (past), Novartis, Pfizer, Methylgene, SigmaTau,Merck, ContraFect Trius, and has received research grants from SOS KidsFoundation, Sharpe Family Foundation, Astellas, Cubist, Theravance, Med-icines Company, Actavis, Pfizer, Merck, Novartis, ContraFect, and TheSchueler Foundation. For activities outside of the submitted work, T. E. Z.has served as a consultant for Astellas, Pfizer, Merck, and Cubist (all past)and has received research grants from Merck (past), Cubist (past), Agencyfor Health Research and Quality, CDC, NIH, and the Thrasher Foundation.All other authors report no potential conflicts. All authors have submittedthe ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflictsthat the editors consider relevant to the content of the manuscript have beendisclosed.

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